Method for treating proliferative disorders associated with mutations in c-Met

ABSTRACT

The present invention relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating c-Met associated cancers, in a subject in need thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/601,729, filed Jul. 8, 2010, which is the U.S. National Stage ofInternational Application No. PCT/US2008/006547, filed May 22, 2008,which claims the benefit of U.S. Application No. 60/691,937, filed May25, 2007. The entire teachings of the above applications areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a method of inhibiting the activity of Hsp90 ina subject in need thereof and methods for treating proliferativedisorders associated with misregulation of c-Met receptor tyrosinekinase (including mutations or fusion proteins that result inconstitutively active c-Met, and mutations that result in amplificationor over expression of c-Met).

BACKGROUND OF THE INVENTION

Although tremendous advances have been made in elucidating the genomicabnormalities that cause malignant cancer cells, currently availablechemotherapy remains unsatisfactory, and the prognosis for the majorityof patients diagnosed with cancer remains dismal.

Heat shock proteins (HSPs) are a class of chaperone proteins that areup-regulated in response to elevated temperature and other environmentalstresses, such as ultraviolet light, nutrient deprivation, and oxygendeprivation. HSPs act as chaperones to other cellular proteins (calledclient proteins) and facilitate their proper folding and repair, and aidin the refolding of misfolded client proteins. There are several knownfamilies of HSPs, each having its own set of client proteins. The Hsp90family is one of the most abundant HSP families, accounting for about1-2% of proteins in a cell that is not under stress and increasing toabout 4-6% in a cell under stress. Inhibition of Hsp90 results indegradation of its client proteins via the ubiquitin proteasome pathway.Unlike other chaperone proteins, the client proteins of Hsp90 are mostlyprotein kinases or transcription factors involved in signaltransduction, and a number of its client proteins have been shown to beinvolved in the progression of cancer.

c-Met is a receptor tyrosine kinase that is a client protein of Hsp90and is encoded by the Met protooncogene. Hepatocyte growth factor (HGF)(also referred to as scatter factor (SF)) is the natural ligand of c-Metwhich binds to c-Met and leads to a variety of cellular responses suchas proliferation, survival, angiogenesis, wound healing, tissueregeneration, scattering, motility, invasion and branching morphogenesis(Ma et al., Cancer and Metastasis Reviews (2003), 22: 309-325). c-Metand HGF are expressed in numerous tissues, although their expression isnormally confined predominantly to cells of epithelial and mesenchymalorigin, respectively. c-Met and HGF are required for normal mammaliandevelopment and have been shown to be important in cell migration, cellproliferation and survival, morphogenic differentiation, andorganization of 3-dimensional tubular structures (e.g., renal tubularcells, gland formation, etc.). However, dysregulation of c-Met and/orHGF is believed to contribute to tumor growth, dissemination andinvasion in several human cancers. c-Met and/or HGF are highly expressedin numerous cancers and their expression correlates with poor prognosis(Christensen, et al., Cancer Research (2003), 63:7345-7355). Forexample, c-Met receptor mutations have been shown to be expressed in anumber of human cancers including hereditary and sporadic humanpapillary renal carcinomas, ovarian cancer, childhood hepatocellularcarcinoma, metastatic head and neck squamous cell carcinomas, esophagealcancer and gastric cancer. Met gene amplification and over expression ofc-Met has been shown to be associated with both non-small cell lungcancer (NSCLC) and small cell lung cancer (SCLC), as well as colorectalcancer, and the Tpr/Met fusion protein has been shown to be present inhuman osteogenic sarcoma and gastric cancer. Families with germinemutations that activate c-Met kinase are prone to multiple kidney tumorsas well as tumors in other tissues. Numerous studies have correlated theexpression of c-Met and/or HGF with the state of disease progression ofdifferent types of cancer (including lung, colon, breast, prostate,liver, pancreas, brain, kidney, ovarian, stomach, skin, and bonecancers).

The validity of targeting receptor tyrosine kinases (RTK) that aredysregulated in human cancers is illustrated by the successes of Gleevectargeting Bcr-Abl in chronic myelogenous leukemia and c-Kit ingastroinstinal stromal tumors, Herceptin in Her-2 overexpressing breastcancers, and Iressa in select NSCLC that have dysregulated EGFR.Compelling evidence exists for targeting c-Met in the treatment of humancancers and several small drug molecules that inhibit c-Met arecurrently in development. However, therapies that target specific RTKoften work well initially for treating cancer but eventually fail due toadditional mutations which allow RTK to maintain its activity in thepresence of the drug. Moreover, the selective c-Met inhibitor SU11274,while highly affected against wild type c-Met and some mutants of c-Met,has been shown to be ineffective against other c-Met mutants (Berthou,et al., Oncogene (2004), 23:5387-5393). Therefore, a need exists todevelop new anticancer therapeutics that reduce the expression and/oractivity of c-Met via a different mechanism than therapeutics thatdirectly inhibit c-Met.

SUMMARY OF THE INVENTION

The present invention provides compounds which inhibit the activity ofHsp90 and thereby increase the degradation of c-Met, a client protein ofHsp90. Thus, compounds of the invention are useful in the treating ofproliferative disorders, such as cancer, including c-Met associatedcancers.

In one embodiment, the present invention provides Hsp90 inhibitorcompounds having the formula (I):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (I), ring A is an aryl or a heteroaryl,wherein the aryl or the heteroaryl are optionally further substitutedwith one or more substituents in addition to R₃;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR7)₂, or —SP(O)(OR₇)₂;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₅ is an optionally substituted heteroaryl or an optionally substituted8 to 14 membered aryl;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In one embodiment, ring A of the compounds of formula (I) is not asubstituted [1,2,3]triazole, and/or compounds represented by formula (I)do not include3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole.

The present invention also provides Hsp90 inhibitor compounds having theformula (II):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (II), ring A, R₁, and R₃ are defined asfor formula (I); and

R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith:

-   -   i) one substituent selected from nitro, cyano, a haloalkoxy, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,        guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,        —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or    -   ii) two to five substituents selected from the group consisting        of an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, an optionally substituted        heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,        nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,        —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁; and

R₂₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl.

In one embodiment, compounds represented by formula (II) do not include3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole,3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole,3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole,or 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.

The present invention also provides Hsp90 inhibitor compounds having theformula (III):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (III), ring A, R₁, and R₃ are definedas for formula (I); and

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

In one embodiment, compounds represented by formula (III) do not includecompounds in which R₁₈ is not cyclohexyl.

The invention also provides Hsp90 inhibitor compounds represented byformula (IV) or formula (V):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formulas (IV) and (V), R₁ and R₃ are defined asfor formula (I); and

X₁₄ is O, S, or NR₇;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

R₂₂, for each occurrence, is independently a substituent selected fromthe group consisting of H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, ahaloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently a substituentselected from the group consisting of H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

In one embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (VI):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, ora prodrug thereof. In formula (VI):

ring A is an aryl or a heteroaryl, wherein the aryl or the heteroarylare optionally further substituted with one or more substituents inaddition to R₃;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₅ is an optionally substituted heteroaryl or an optionally substituted8 to 14-membered aryl;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In another embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (VII):

In formula (VII), R₂′ is an optionally substituted phenyl group.Preferably, R₂′ is substituted with one or more group represented byR₃₀, wherein R₃₀, for each occurrence, is independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. The remainder of the variables in structural formula (VII)have values defined above with reference to structural formula (VI).

In another embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (VIII):

In formula (VIII), R₁₈ is an optionally substituted cycloalkyl, andoptionally substituted cycloalkenyl, or a substituted alkyl, wherein thealkyl group is substituted with one or more substituents independentlyselected from the group consisting of an optionally substituted alkynyl,an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁. The remainder of thevariables in structural formula (VIII) have values defined above withreference to structural formula (VI).

In another embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (IX):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, ora prodrug thereof. In formula (IX):

ring A is an aryl or a heteroaryl, wherein the aryl or the heteroarylare optionally further substituted with one or more substituents inaddition to R₃;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₅ is an optionally substituted heteroaryl or an optionally substituted8 to 14-membered aryl;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In another embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (X):

In formula (X), R₂′ is an optionally substituted phenyl group.Preferably, R₂′ is substituted with one or more group represented byR₃₀, wherein R₃₀, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. The remainder of the variables in structural formula (X)have values defined above with reference to structural formula (IX).

In another embodiment, the present invention provides Hsp90 inhibitorcompounds represented by structural formula (XI):

In formula (XI), R₁₈ is an optionally substituted cycloalkyl, andoptionally substituted cycloalkenyl, or a substituted alkyl, wherein thealkyl group is substituted with one or more substituents independentlyselected from the group consisting of an optionally substituted alkynyl,an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁. The remainder of thevariables in structural formula (XI) have values defined above withreference to structural formula (IX).

In another embodiment, the present invention is a method of inducingdegradation of a c-Met protein in a subject. The method comprisesadministering to the subject an effective amount of a compound of theinvention.

In another embodiment, the present invention is a method of treating ac-Met associated cancer (e.g., a cancer which exhibits dysregulatedc-Met and/or HGF) in a subject. The method comprises administering tothe subject an effective amount of a compound of the invention.

In another embodiment, the invention relates to a method of treatingcancer in a subject, comprising:

-   -   a) determining whether the subject has a c-Met associated        cancer; and    -   b) administering to the subject an effective amount of compound        of the invention, if the subject has a c-Met associated cancer.

In another embodiment, the present invention is a pharmaceuticalcomposition for treating a c-Met associated cancer, comprising acompound of the invention and a pharmaceutically acceptable carrier. Thepharmaceutical compositions can be used in therapy, e.g., to inhibitHsp90 activity in a mammal in need of such inhibition, to treat a mammalwith a proliferative disorder, or to treat a mammal with cancer, forexample a c-Met associated cancer. Preferably, the mammal is a human. Inanother embodiment, the pharmaceutical composition includes anadditional therapeutic agent. In another embodiment, the additionaltherapeutic agent is an anticancer agent.

In another embodiment of the present invention is the use of a compoundof the invention for the manufacture of a medicament for inhibitingHsp90 in a mammal in need of such inhibition or for treating a mammalwith cancer, for example a c-Met associated cancer.

The compounds shown in Tables 5, 6, and 7, or compounds of any formulaherein, or tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof, inhibit theactivity of Hsp90 and, thereby cause the degradation of Hsp90 clientproteins, such as c-Met. Hsp90 is necessary for the survival of normaleukaryotic cells. However, Hsp90 is over expressed in many tumor typesindicating that it may play a significant role in the survival of cancercells and that cancer cells may be more sensitive to inhibition of Hsp90than normal cells. Thus, the compounds shown in Table 5, 6, or 7, orcompounds of any formula herein, or tautomers, pharmaceuticallyacceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugsthereof, are useful treating cancer, such as c-Met associated cancers.

Although chemotherapeutic agents initially cause tumor regression, mostagents that are currently used to treat cancer target only one pathwayto tumor progression. Therefore, in many instances, after treatment withone or more chemotherapeutic agents, a tumor develops multidrugresistance and no longer responses positively to treatment. One of theadvantages of inhibiting Hsp90 activity is that several of its clientproteins, which are mostly protein kinases or transcription factorsinvolved in signal transduction, have been shown to be involved in theprogression of cancer. Thus, inhibition of Hsp90 provides a method ofshort circuiting several pathways for tumor progression simultaneously.Moreover, treatment of cancers with kinase inhibitors, such as Gleevec,has been shown to be initially highly successful but ultimately fails inmost cases because the inhibited kinase develops one or more mutationthat makes it resistant to the kinase inhibitor. Therefore, treatment ofcancers with an Hsp90 inhibitor of the invention either alone, or incombination with other chemotherapeutic agents, is more likely to resultin regression or elimination of the cancer, and less likely to result inthe development of more aggressive multidrug resistant cancers thanother currently available therapeis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the ATPase activity of Hsp90 when untreated,when treated with 40 mM of Geldanamycin, a known Hsp90 inhibitor as apositive control, and when treated with 40 μM or 4 μM of Compound 108 ofthe invention.

FIG. 2 is gel showing the amount of Her2, an Hsp90 client protein, incells that are untreated, in cells that have been treated with 0.5 μM, 2μM, or 5 μM of 17AAG, a known Hsp90 inhibitor, and in cells that havebeen treated with 0.5 μM, 2 μM, or 5 μM of Compound 108 or Compound 49.

FIG. 3 is a Western blot analysis of the c-Met from NCI-H1193 cellstreated with Hsp90 inhibitors of the invention or 17AAG (as a positivecontrol).

FIG. 4 is a graph showing an FACSCalibur flow cytometer analysis ofc-Met on the surface of ACHN human renal cell carcinoma cells aftertreated with Compound 226 of the invention, 17AAG (as a positivecontrol) or 17DMAG (as a positive control). The results indicate thatthe Hsp90 inhibitors of the invention induce c-Met degradation at alower concentration than 17AAG or 17DMAG.

FIG. 5 is a graph showing an FACSCalibur flow cytometer analysis ofc-Met on the surface of MKN45 human gastric carcinoma cells aftertreated with Compound 226 of the invention, 17AAG (as a positivecontrol) or 17DMAG (as a positive control). The results indicate thatthe Hsp90 inhibitors of the invention induce c-Met degradation at alower concentration than 17AAG or 17DMAG.

FIG. 6 is a graph of showing cell survival of MKN-45 human gastriccarcinoma cells, which carry an amplified c-Met locus, after treatmentwith Compound 226 of the invention or after treatment with 17AAG orDMAG.

FIG. 7 shows the results of a nude mouse xenograft study to determinethe effects of Compound #226 on the in vivo growth rate of the humanc-MET amplified gastric carcinoma tumor cell line MKN-45. Tumor bearinganimals (8 mice/group) were i.v. injected 3 time per week for a total of9 doses (arrowheads) and the average tumor volumes for each group (errorbars represent SEM) were determined every 3-4 days. Treatment with adose of 50 mg/kg body weight of Compound #226 substantially inhibitedtumor growth, with a % T/C value of 8 observed on day 36 (indicated onright). Overt toxicity was not observed, with the 50 mg/kg Compound#226-treated group having an average bodyweight loss relative to thestart of the study of −3.5% (+/−0.8 SEM) on day 36.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds and uses of said compounds. Thepresent invention encompasses the use of the compounds of the inventionto inhibit Hsp90 activity and for the treatment of a proliferativedisorder, such as cancer, including c-Met associated cancers. Inparticular, the present invention encompasses the use of compounds ofthe invention to slow or stop the growth of c-Met associated cancerouscells, to reduce metastasis of cancerous cells, and/or to reduce oreliminate cancerous cells in a mammal.

In certain embodiments, the compounds of the invention can be used incombination with other chemotherapeutic agents and may help to preventor reduce the development of multidrug resistant cancerous cells in amammal. In this embodiment, the compounds of the invention may allow areduced efficacious amount of a second chemotherapeutic agent given to amammal. In addition, compounds of the invention are expected to beefficacious against cancers that has become resistant to chemotherapywith c-Met tyrosine kinase inhibits, such as SU11274.

A. Terminology

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl andn-decyl; while saturated branched alkyls include isopropyl, sec-butyl,isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl,2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl,2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Theterm “(C₁-C₆)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative(C₁-C₆)alkyl groups are those shown above having from 1 to 6 carbonatoms. Alkyl groups included in compounds of this invention may beoptionally substituted with one or more substituents.

As used herein, the term “alkenyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched (C₂-C₁₀)alkenyls include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups may be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl,1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical having from 3 to 20 carbon atoms.Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, -cyclodecyl, octahydro-pentalenyl, and the like. Cycloalkylgroups may be optionally substituted with one or more substituents.

As used herein, the term “cycloalkenyl” means a mono- or poly-cyclicnon-aromatic alkyl radical having at least one carbon-carbon double bondin the cyclic system and from 3 to 20 carbon atoms. Representativecycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl,cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl,cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl,1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups maybe optionally substituted with one or more substituents.

As used herein, the term “haloalkyl” means and alkyl group in which oneor more (including all) the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. The term “halomethyl” means a methyl in which one to threehydrogen radical(s) have been replaced by a halo group. Representativehaloalkyl groups include trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

As used herein, an “alkoxy” is an alkyl group which is attached toanother moiety via an oxygen linker.

As used herein, a “haloalkoxy” is an haloalkyl group which is attachedto another moiety via an oxygen linker.

As used herein, the term an “aromatic ring” or “aryl” means ahydrocarbon monocyclic or polycyclic radical in which at least one ringis aromatic. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substitutedwith one or more substituents. In one embodiment, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms, referred toherein as “(C₆)aryl.”

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C₁-C₆)alkylene group. Representative aralkylgroups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.Aralkyl groups may be optionally substituted with one or moresubstituents.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “(C₁-C₆)alkylene” refers to analkylene group that has from one to six carbon atoms. Straight chain(C₁-C₆)alkylene groups are preferred. Non-limiting examples of alkylenegroups include methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), and the like. Alkylenegroups may be optionally substituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic (typicallyhaving 3- to 10-members) or a polycyclic (typically having 7- to20-members) heterocyclic ring system which is either a saturated ring oran unsaturated non-aromatic ring. A 3- to 10-membered heterocycle cancontain up to 5 heteroatoms; and a 7- to 20-membered heterocycle cancontain up to 7 heteroatoms. Typically, a heterocycle has at least oncarbon atom ring member. Each heteroatom is independently selected fromnitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; andsulfur, including sulfoxide and sulfone. The heterocycle may be attachedvia any heteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents. Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaromatic”, “heteroaryl” or like termsmeans a monocyclic or polycyclic heteroaromatic ring comprising carbonatom ring members and one or more heteroatom ring members. Eachheteroatom is independently selected from nitrogen, which can beoxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. Representative heteroaryl groups include pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, atriazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, theheteroaromatic ring is selected from 5-8 membered monocyclic heteroarylrings. The point of attachment of a heteroaromatic or heteroaryl ring toanother group may be at either a carbon atom or a heteroatom of theheteroaromatic or heteroaryl rings. Heteroaryl groups may be optionallysubstituted with one or more substituents.

As used herein, the term “(C₅)heteroaryl” means an aromatic heterocyclicring of 5 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, sulfur ornitrogen. Representative (C₅)heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.

As used herein, the term “(C₆)heteroaryl” means an aromatic heterocyclicring of 6 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, nitrogen orsulfur. Representative (C₆)heteroaryls include pyridyl, pyridazinyl,pyrazinyl, triazinyl, tetrazinyl and the like.

As used herein, the term “heteroaralkyl” means a heteroaryl group thatis attached to another group by a (C₁-C₆)alkylene. Representativeheteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl,imidazol-4-yl-methyl and the like. Heteroaralkyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include any substituent which will form a stablecompound of the invention. Examples of substituents for an alkyl,alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, aralkyl, heteroaryl, and heteroarylalkyl include an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₂₈R₂₉, —C(S)NR₂₈R₂₉, —C(NR₃₂)NR₂₈R₂₉, —NR₃₀C(O)R₃₁,—NR₃₀C(S)R₃₁, —NR₃₀C(NR₃₂)R₃₁, halo, —OR₃₀, cyano, nitro, haloalkoxy,—C(O)R₃₀, —C(S)R₃₀, —C(NR₃₂)R₃₀, —NR₂₈R₂₉, —C(O)OR₃₀, —C(S)OR₃₀,—C(NR₃₂)OR₃₀, —OC(O)R₃₀, —OC(S)R₃₀, —OC(NR₃₂)R₃₀, —NR₃₀C(O)NR₂₈R₂₉,—NR₃₀C(S)NR₂₈R₂₀, —NR₃₀C(NR₃₂)NR₂₈R₂₉, —OC(O)NR₂₈R₂₉, —OC(S)NR₂₈R₂₉,—OC(NR₃₂)NR₂₈R₂₉, —NR₃₀C(O)OR₃₁, —NR₃₀C(S)OR₃₁, —NR₃₀C(NR₃₂)OR₃₁,—S(O)_(h)R₃₀, —OS(O)_(p)R₃₀, —NR₃₀S(O)_(p)R₃₀, —S(O)_(p)NR₂₈R₂₉,—OS(O)_(p)NR₂₈R₂₉, or —NR₃₀S(O)_(p)NR₂₈R₂₉, wherein R₂₈ and R₂₉, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₂₈and R₂₉ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl.

R₃₀ and R₃₁ for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; and

R₃₂, for each occurrence is, independently, H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, —C(O)R₃₀,—C(O)NR₂₈R₂₉, —S(O)_(p)R₃₀, or —S(O)_(p)NR₂₈R₂₉; and

h is 0, 1 or 2.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent, thenitrogen may be a quaternary nitrogen.

As used herein, the terms “subject”, “patient” and “mammal” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),preferably a mammal including a non-primate (e.g., a cow, pig, horse,sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate(e.g., a monkey, chimpanzee and a human), and more preferably a human.In one embodiment, the subject is a non-human animal such as a farmanimal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat,guinea pig or rabbit). In a preferred embodiment, the subject is ahuman.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, “lower alkoxy” refers to“—O—(C₁-C₄)alkyl and a “lower alkenyl” or “lower alkynyl” refers to analkenyl or alkynyl radical having from 2 to 4 carbon atoms,respectively.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as (without limitation) carboxy,hydroxy, thiol, and amino moieties) also include protected derivativesthereof. “Protected derivatives” are those compounds in which a reactivesite or sites are blocked with one ore more protecting groups. Examplesof suitable protecting groups for hydroxyl groups include benzyl,methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate,and the like. Examples of suitable amine protecting groups includebenzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiolprotecting groups include benzyl, tert-butyl, acetyl, methoxymethyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of formula (I) through (LXXII) and Tables 5,6, and 7, or a pharmaceutically acceptable salt, solvate, clathrate,hydrate, polymorph or prodrug thereof, and also include protectedderivatives thereof.

Compounds of the invention may contain one or more chiral centers and/ordouble bonds and, therefore, exist as stereoisomers, such as double-bondisomers (i.e., geometric isomers), enantiomers, or diastereomers.According to this invention, the chemical structures depicted herein,including the compounds of this invention, encompass all of thecorresponding compounds' enantiomers, diastereomers and geometricisomers, that is, both the stereochemically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometricisomeric mixtures). In some cases, one enantiomer, diastereomer orgeometric isomer will possess superior activity or an improved toxicityor kinetic profile compared to other isomers. In those cases, suchenantiomers, diastereomers and geometric isomers of compounds of thisinvention are preferred.

When a disclosed compound is named or depicted by structure, it is to beunderstood that solvates (e.g., hydrates) of the compound or itspharmaceutically acceptable salts are also included. “Solvates” refer tocrystalline forms wherein solvent molecules are incorporated into thecrystal lattice during crystallization. Solvate may include water ornonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid,ethanolamine, and EtOAc. Solvates, wherein water is the solvent moleculeincorporated into the crystal lattice, are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water.

When a disclosed compound is named or depicted by structure, it is to beunderstood that the compound, including solvates thereof, may exist incrystalline forms, non-crystalline forms or a mixture thereof. Thecompounds or solvates may also exhibit polymorphism (i.e. the capacityto occur in different crystalline forms). These different crystallineforms are typically known as “polymorphs.” It is to be understood thatwhen named or depicted by structure, the disclosed compounds andsolvates (e.g., hydrates) also include all polymorphs thereof.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. One of ordinary skill inthe art will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used in solidfying thecompound. For example, changes in temperature, pressure, or solvent mayresult in different polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

When a disclosed compound is named or depicted by structure, it is to beunderstood that clathrates (“inclusion compounds”) of the compound orits pharmaceutically acceptable salts, solvates or polymorphs are alsoincluded. “Clathrate” refers to a chemical substance consisting of alattice of one type of molecule trapping and containing a second type ofmolecule. For examples, the a clathrate can be compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds offormula (I) through (LXXII) and Tables 5, 6, and 7 that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of compounds of formula (I)through (LXXII), and Tables 5, 6, and 7, that comprise —NO, —NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5^(th)ed).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as improvedwater solubility, improved circulating half-life in the blood (e.g.,because of reduced metabolism of the prodrug), improved uptake, improvedduration of action, or improved onset of action; or 2) is itselfbiologically inactive but is converted in vivo to a biologically activecompound. Examples of biohydrolyzable amides include, but are notlimited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides,and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, “Hsp90” includes each member of the family of heat shockproteins having a mass of about 90-kiloDaltons. For example, in humansthe highly conserved Hsp90 family includes cytosolic Hsp90α and Hsp90βisoforms, as well as GRP94, which is found in the endoplasmic reticulum,and HSP75/TRAP1, which is found in the mitochondrial matrix.

c-Met is a receptor tyrosine kinase that is expressed in normal andmalignant cells and has been identified as a proto-oncogene. HGF/c-Metsignaling triggers an invasive growth program that is thought to beessential in early embryonic development but when dysregulated canresult malignant growth, motility, migration and invasion by a mechanismthat is not yet completely understood. The human Met gene is located onchromosome 7 band 7q21-q31 and spans more than 120 kb (Ma, et al.,Cancer and Metastasis Reviews (2003), 22:309-325). In wild type cells,c-Met is a heterodimer that consists of an extracellular α-subunit and aβ-subunit with a large extracellular domain, a membrane spanning segmentand an intracellular tyrosine kinase domain. Functional structures anddomains of c-Met include 1) Sema domain at the N-terminus which includesa MRS cysteine-rich region; 2) PSI domain which is also found inplexins, semaphorins and integrins; 3) IPT repeats which are found inimmunoglobulin, plexins and transcription factors; 4) transmembranedomain; 5) juxtamembrane domain; and 6) the intracellular tyrosinekinase domain at the C-terminus.

Activation of c-Met signaling is dependent on phosphorylation ofmultiple residues on c-Met. Upon binding of HGF, c-Met undergoesautophosphorylation at Y1230, Y1234, and Y1235 in the activation loop ofthe tyrosine kinase domain which activates the kinase activity of c-Met.Y1313 can also be phosphorylated in response to HGF binding and isimportant in binding PI3-K which is implicated in prosurvival signaling.Phosphorylation of Y1349 and Y1356 at the C-terinus of c-Met activatesthe multisubstrate signal transducer docking site which has beenimplicated in Met-mediated signal transduction and mediates theinteractions of SHC, Src, and Gab1, while recruitment of Grb2, PI3-K,PLC-γ and SHP2 is dependent on phosphorylation of Y1356 alone.Regultation of cell morphogenesis is mediated via Y1365. Phosphorylationof the Y1003 residue in the juxtamembrane domain mediates the binding ofc-Cbl. c-Cbl acts as a negative regulator protein of c-Met by promotingthe polyubiquitinization of c-Met which leads to degradation.

Dysregulation of HGF/c-Met signaling can be caused by 1) increasedexpression of HGF; 2) activating mutations which typically occur in thetyrosine kinase domain or the juxtamembrane domain of c-Met and conferconstitutive kinase activity; 3) intra-chromosomal amplification of theMet gene and over expression of c-Met; 4) chromosomal translocation suchas in the Trp/Met fusion protein which results in the loss of thejuxtamembrane domain and leads to constitutive activation; and 5)alternate splicing variants c-Met mRNA which lead to loss of thejuxtamembrane domain and also lead to constitutive activation.

Activating mutation in the tyrosine kinase domain or in thejuxtamembrane domain of c-Met which result in increased activation ofthe tyrosine kinase activity have been observed in hereditary andsporatic papillary renal carcinoma, ovarian cancer, hepatocellularcarcinoma, metastatic head and neck squamous cell carcinomas, NSCLC,SCLC, glioma, breast cancer, and gastric cancer. In somatic papillaryrenal cell carcinoma activating mutations have been found at amino acidresidues M1268 (e.g., M1268T), Y1248 (e.g., Y1248D, Y1248H), Y1246(e.g., Y1246H), Y1230 (e.g., Y1230C), L1213 (e.g., L1213V), H1124 (e.g.,H1124D, H1112L, and H1112Y), and V1110 (V1110I). In germline papillaryrenal cell carcinoma activating mutations have been found at amino acidresidues Y1248 (e.g., Y1248C), Y1246 (e.g., Y1246N), V1238 (e.g.,V1238I), Y1230 (e.g., Y1230C and Y1230H), V1206 (e.g., V1206L), M1149(e.g., M1149T), and H1112 (e.g., H1112R). In hepatocellular carcinomaactivating mutations have been found at amino acid residues M1268 (e.g.,M1268I), K1262 (e.g., K1262R), and T1191 (e.g., T1191I). In head andneck squamous cell carcinoma activating mutations have been found atamino acid residues Y1253 (e.g., Y1253D), Y1235 (e.g., Y1235D), andY1230 (e.g., Y1230C and Y1230D). In glioma activating mutations havebeen found at amino acid residue G1137 (e.g., G1137V). In NSCLCactivating mutations have been found at amino acid residue T1010 (e.g.,T1010I). In SCLC activating mutations have been found at amino acidresidues R988 (e.g., R988C) and T1010 (e.g., T1010I). In breast canceractivating mutations have been found at amino acid residues T1010 (e.g.,T1010I). In gastric cancer activating mutations have been found at aminoacid residue P1009 (e.g., P1009S) Amino acids listed herein for c-Metare numbered as in Schmit, et al., Onogene (1999), 18:2343-2350.Compounds of the invention cause the degradation of c-Met and can beused either alone or in combination with other anticancer therapies totreat patients with cancers that have activating mutations in thetyrosine kinase domain or in the juxtamembrane domain of c-Met.

The juxtamembrane of receptor tyrosine kinases has been shown to represscatalytic function and mutation in the juxtamembrane relieve thisrepression and can lead to oncogenesis. The Tpr/Met fusion proteinresults from replacement of the 5′ region of the Met gene with Tpr whichprovides two strong dimerization motifs. Dimerization activates the Metkinase activity and results in transforming and metastatic properties.The Tpr/Met fusion protein has been found in gastric cancer and resultsin increased Met kinase activity. In addition, an alternative splicingform of Met mRNA has been found in small cell lung cancer which resultsin skipping the juxtamembrane domain. Loss of the juxtamembrane domainleads to increased Met kinase activity and oncogenesis. Compounds of theinvention cause the degradation of c-Met and can be used either alone orin combination with other anticancer therapies to treat patients withcancers that have juxtamembrane mutations or deletions in c-Met.

Amplification of the Met gene and overexpression of c-Met has been foundin several types of cancers including gastric cancer, esophageal cancer,small cell lung cancer, non-small cell lung cancer, breast cancer,multiple myeloma, and colorectal cancer metastases. Compounds of theinvention cause the degradation of c-Met and can be used either alone orin combination with other anticancer therapies to treat patients withcancers that have Met gene amplification and/or c-Met overexpression.

Met amplification and mutation has also been implicated as a strategy bywhich certain cancers become resistant to therapy (e.g., chemotherapy orradiation therapy). For example, certain non-small cell lung cancerscontain an activating mutation in receptor tyrosine kinase EGFR whichresults in oncogenesis. Most EGFR mutant NSCLCs initially respond toEGFR inhibitors such as Iressa and Tarceva but the vast majority ofthese tumors ultimately become resistant to the drug. A subset of theseresistant cancers have been shown to have amplified Met, and it isthought that Met amplification is a mechanisms of acquired resistance,and in particular acquired resistance to kinase inhibitors such asIressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF, andc-Kit inhibitor) (Engelman et al., Sciencexpress,www.sciencexpress.org/26 Apr. 2007/page 1/10.1126/science. 1141478).Compounds of the invention cause the degradation of c-Met and can beused either alone or in combination with other anticancer therapies,such as treatment with kinase inhibitors, to treat patients with cancerthat has become resistant to other anticancer therapies.

As used herein, the term “c-Met associated cancer” refers to a cancerwhich has aberrant expression and/or activation of c-Met which causes orenhances growth or metastasis of the cancer. For example, c-Metassociated cancers include cancer that have 1) increased expression ofHGF; 2) activating mutations which typically occur in the tyrosinekinase domain or the juxtamembrane domain of c-Met and confer increaseor constitutive kinase activity; 3) intra-chromosomal amplification ofthe Met gene and over expression of c-Met; 4) chromosomal translocationsuch as in the Trp/Met fusion protein which results in the loss of thejuxtamembrane domain and leads to constitutive activation; or 5)alternate splicing variants c-Met mRNA which lead to loss of thejuxtamembrane domain and also lead to constitutive activation. Any ofthe above defects in c-Met regulation indicate that a cancer is a c-Metassociated cancer and can be assayed for by methods known to thoseskilled in the art.

As used herein, the term “tyrosine kinase inhibitor” refers to ananticancer agent, such as a small molecule or protein that inhibits theactivity of one or more tyrosine kinase. In one embodiment, the tyrosinekinase inhibitor inhibits the tyrosine kinase by binding directly to itand inhibiting its kinase activity. Examples of tyrosine kinaseinhibitors include Iressa and Tarceva (EGFR inhibitors), Gleevec (aBcr-Abl, PDGF, and c-Kit inhibitor), and SU11274 (a c-Met inhibitor).

As used herein, the term “tyrosine kinase inhibitor that does notinhibit c-Met” refers to an anticancer agent, such as a small moleculeor protein that inhibits the activity of one or more tyrosine kinase butdoes not substantially inhibit the kinase activity of c-Met. A tyrosinekinase inhibitor does not substantially inhibit the kinase activity ofc-Met if it does not affect the phosphorylation pattern of c-Met incells that are treated with up to 10 μM of the tyrosine kinaseinhibitor.

The phrase “gene amplification,” as used herein, means the selectivesynthesis of a DNA fragment that results in multiple copies of the Metgene or fragment of the chromosome in which Met is encoded.

The term “level of expression” or “expression level” generally refers tothe amount of an amino acid product or protein in the sample, preferablythe amount of a phosphorylated amino acid product or phosphorylatedprotein in the sample according to the invention. “Expression” refers tothe process by which gene coded information is converted into proteinsoperating in the cell. As used herein, “expressed genes” include thosethat are transcribed into mRNA and then translated into protein. Theterms “overexpression” refers to an upward deviation in levels ofexpression as compared to the baseline expression level in non-canceroustissue of the same type. “Overexpression” is therefore also “increasedexpression”.

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g.,diabetic retinopathy or other retinopathies, cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated or prevented by the methods of the present inventioninclude, but are not limited to human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by theK562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line);myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B. C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

In one embodiment, the disclosed method is believed to be particularlyeffective in treating subject with non-solid tumors such as multiplemyeloma. In another embodiment, the disclosed method is believed to beparticularly effective against T-leukemia (e.g., as exemplified byJurkat and CEM cell lines); B-leukemia (e.g., as exemplified by the SBcell line); promyelocytes (e.g., as exemplified by the HL-60 cell line);uterine sarcoma (e.g., as exemplified by the MES-SA cell line);monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line);and lymphoma (e.g., as exemplified by the U937 cell line).

In one embodiment, the compounds of the invention are believed to beparticularly effective in treating a subject with c-Met associatedcancers.

Some of the disclosed methods can be particularly effective at treatingsubjects whose cancer has become “multi-drug resistant”. A cancer whichinitially responded to an anti-cancer drug, such as a tyrosin kinaseinhibitor, becomes resistant to the anti-cancer drug when theanti-cancer drug is no longer effective in treating the subject with thecancer. For example, many tumors will initially respond to treatmentwith an anti-cancer drug by decreasing in size or even going intoremission, only to develop resistance to the drug. Drug resistant tumorsare characterized by a resumption of their growth and/or reappearanceafter having seemingly gone into remission, despite the administrationof increased dosages of the anti-cancer drug. Cancers that havedeveloped resistance to two or more anti-cancer drugs are said to be“multi-drug resistant”. For example, it is common for cancers to becomeresistant to three or more anti-cancer agents, often five or moreanti-cancer agents and at times ten or more anti-cancer agents.

In one embodiment, the compounds of the invention are believed to beparticularly effective in treating a subject that has a cancer that hasbecome resistant to treatment with one or more tyrosine kinaseinhibitor. In another embodiment, the compounds of the invention arebelieved to be particularly effective in treating a subject that has acancer that has become resistant to treatment with a c-Met inhibitor. Inanother embodiment, the compounds of the invention are believed to beparticularly effective in treating a subject that has a cancer that hasbecome resistant to treatment with a tyrosine kinase inhibitor that doesnot substantially inhibit c-Met.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from, for example, an acid and a basic group of one of thecompounds of formula (I) through (LXXII) and Tables 5, 6, and 7.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, besylate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of formula (I) through (LXXII) and Tables 5, 6, and 7 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of formula (I) through (LXXII) and Tables 5, 6,and 7 having a basic functional group, such as an amine functionalgroup, and a pharmaceutically acceptable inorganic or organic acid.Suitable acids include, but are not limited to, hydrogen sulfate, citricacid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogenbromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide,phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartraticacid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaricacid, gluconic acid, glucaronic acid, formic acid, benzoic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds of formula (I)through (LXXII) and Tables 5, 6, and 7. The term solvate includeshydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate,tetrahydrate, and the like).

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, i.e.,non-toxic, non-inflammatory, non-immunogenic and devoid of otherundesired reactions upon the administration to a subject. Standardpharmaceutical formulation techniques can be employed, such as thosedescribed in Remington's Pharmaceutical Sciences, ibid. Suitablepharmaceutical carriers for parenteral administration include, forexample, sterile water, physiological saline, bacteriostatic saline(saline containing about 0.9% mg/ml benzyl alcohol), phosphate-bufferedsaline, Hank's solution, Ringer's-lactate and the like. Methods forencapsulating compositions (such as in a coating of hard gelatin orcyclodextran) are known in the art (Baker, et al., “Controlled Releaseof Biological Active Agents”, John Wiley and Sons, 1986).

As used herein, the term “effective amount” refers to an amount of acompound of this invention which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of a proliferativedisorder, prevent the advancement of a proliferative disorder, cause theregression of a proliferative, prevent the recurrence, development,onset or progression of a symptom associated with a proliferativedisorder, or enhance or improve the prophylactic or therapeuticeffect(s) of another therapy. The precise amount of compoundadministered to a subject will depend on the mode of administration, thetype and severity of the disease or condition and on the characteristicsof the subject, such as general health, age, sex, body weight andtolerance to drugs. It will also depend on the degree, severity and typeof cell proliferation, and the mode of administration. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors. When co-administered with other agents, e.g., whenco-administered with an anti-cancer agent, an “effective amount” of thesecond agent will depend on the type of drug used. Suitable dosages areknown for approved agents and can be adjusted by the skilled artisanaccording to the condition of the subject, the type of condition(s)being treated and the amount of a compound of the invention being used.In cases where no amount is expressly noted, an effective amount shouldbe assumed.

Non-limiting examples of an effective amount of a compound of theinvention are provided herein below. In a specific embodiment, theinvention provides a method of preventing, treating, managing, orameliorating a proliferative disorder or one or more symptoms thereof,said methods comprising administering to a subject in need thereof adose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, atleast 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more ofone or more compounds of the invention once every day, preferably, onceevery 2 days, once every 3 days, once every 4 days, once every 5 days,once every 6 days, once every 7 days, once every 8 days, once every 10days, once every two weeks, once every three weeks, or once a month.

The dosages of a chemotherapeutic agents other than compounds of theinvention, which have been or are currently being used to prevent,treat, manage, or ameliorate a proliferative disorder, or one or moresymptoms thereof, can be used in the combination therapies of theinvention. Preferably, dosages lower than those which have been or arecurrently being used to prevent, treat, manage, or ameliorate aproliferative disorder, or one or more symptoms thereof, are used in thecombination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorder, or one or more symptomsthereof, can obtained from any reference in the art including, but notlimited to, Hardman et al., eds., 1996, Goodman & Gilman's ThePharmacological Basis Of Basis Of Therapeutics 9^(th) Ed, McGraw-Hill,New York; Physician's Desk Reference (PDR) 57^(th) Ed., 2003, MedicalEconomics Co., Inc., Montvale, N.J., which are incorporated herein byreference in its entirety.

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a proliferative disorder, or the amelioration of one or moresymptoms (preferably, one or more discernible symptoms) of aproliferative disorder resulting from the administration of one or moretherapies (e.g., one or more therapeutic agents such as a compound ofthe invention). In specific embodiments, the terms “treat”, “treatment”and “treating” refer to the amelioration of at least one measurablephysical parameter of a proliferative disorder, such as growth of atumor, not necessarily discernible by the patient. In other embodimentsthe terms “treat”, “treatment” and “treating” refer to the inhibition ofthe progression of a proliferative disorder, either physically by, e.g.,stabilization of a discernible symptom, physiologically by, e.g.,stabilization of a physical parameter, or both. In other embodiments theterms “treat”, “treatment” and “treating” refer to the reduction orstabilization of tumor size or cancerous cell count.

As used herein, the terms “prevent”, “prevention” and “preventing” referto the reduction in the risk of acquiring or developing a givenproliferative disorder, or the reduction or inhibition of the recurrenceor a proliferative disorder. In one embodiment, a compound of theinvention is administered as a preventative measure to a patient,preferably a human, having a genetic predisposition to any of thedisorders described herein.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment, management, oramelioration of a proliferative disorder or one or more symptomsthereof. In certain embodiments, the term “therapeutic agent” refers toa compound of the invention. In certain other embodiments, the term“therapeutic agent” refers does not refer to a compound of theinvention. Preferably, a therapeutic agent is an agent which is known tobe useful for, or has been or is currently being used for the treatment,management, prevention, or amelioration a proliferative disorder or oneor more symptoms thereof.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent), which is more effective than the additive effects ofthe therapies. A synergistic effect of a combination of therapies (e.g.,a combination of prophylactic or therapeutic agents) permits the use oflower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject with a proliferativedisorder. The ability to utilize lower dosages of a therapy (e.g., aprophylactic or therapeutic agent) and/or to administer said therapyless frequently reduces the toxicity associated with the administrationof said therapy to a subject without reducing the efficacy of saidtherapy in the prevention, management or treatment of a proliferativedisorder. In addition, a synergistic effect can result in improvedefficacy of agents in the prevention, management or treatment of aproliferative disorder. Finally, a synergistic effect of a combinationof therapies (e.g., a combination of prophylactic or therapeutic agents)may avoid or reduce adverse or unwanted side effects associated with theuse of either therapy alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapy (e.g., a prophylactic or therapeuticagent). Side effects are always unwanted, but unwanted effects are notnecessarily adverse. An adverse effect from a therapy (e.g.,prophylactic or therapeutic agent) might be harmful or uncomfortable orrisky. Side effects include, but are not limited to fever, chills,lethargy, gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the term “in combination” refers to the use of more thanone therapies (e.g., one or more prophylactic and/or therapeuticagents). The use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a proliferative disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compound ofthe invention) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent such as ananti-cancer agent) to a subject with a proliferative disorder, such ascancer.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a proliferativedisorder or one or more symptoms thereof.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use and includeprophylactic and therapeutic protocols.

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), which does not result in a cure ofthe disease. In certain embodiments, a subject is administered one ormore therapies (e.g., one or more prophylactic or therapeutic agents) to“manage” a disease so as to prevent the progression or worsening of thedisease.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to a chiral center inthe molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of the invention.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or diastereomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are administered inisolated form or as the isolated form in a pharmaceutical composition.As used herein, “isolated” means that the compounds of the invention areseparated from other components of either (a) a natural source, such asa plant or cell, preferably bacterial culture, or (b) a syntheticorganic chemical reaction mixture. Preferably, the compounds of theinvention are purified via conventional techniques. As used herein,“purified” means that when isolated, the isolate contains at least 95%,preferably at least 98%, of a compound of the invention by weight of theisolate either as a mixture of stereoisomers or as a diastereomeric orenantiomeric pure isolate. An “isolated agent” can be a synthetic ornaturally occurring molecule having a molecular weight of about 1000daltons or less, or a natural product having a molecular weight ofgreater than 1000 daltons. For example, an isolated agent can be anantibody, or fragment thereof, or an antibiotic.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

B. The Compounds of the Invention

The present invention encompasses compounds having formula (I) through(LXXII), or any embodiment thereof, or a compound shown in Table 5, 6,or 7, and tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect,the invention provides compounds of formula (I) as set forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein ring A, R₁, R₃ and R₅ are defined asabove.

Compounds of formula (I) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (I) are particularlyuseful in treating cancer when given in combination with otheranti-cancer agent.

In one embodiment, in the compounds of formula (I), R₅ is an optionallysubstituted naphthyl.

In another embodiment, in the compounds of formula (I), R₅ isrepresented by the following formula:

wherein:

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and

m is zero or an integer from 1 to 7, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment, in the compounds represented by formula (I), R₅is represented by one of the following formulas:

wherein R₉ is defined as above;

q is zero or an integer from 1 to 7; and

u is zero or an integer from 1 to 8.

In another embodiment, in the compounds represented by formula (I), R₅is selected from the group consisting of:

wherein:

X₆, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₆ groups are independently selected fromCH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₇ groups are independently selected fromCH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, CR₉R₉, O, S, S(O)p,NR₇, or NR₁₇;

X₉, for each occurrence, is independently N or CH;

X₁₀, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₀ is selected from CH and CR₉;

R₁₇, for each occurrence, is independently —H, an alkyl, an aralkyl,—C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; wherein R₇, R₉, R₁₀, R₁₁ and p aredefined as above.

In another embodiment, in the compounds represented by formula (I), R₅is an optionally substituted indolyl, an optionally substitutedbenzoimidazolyl, an optionally substituted indazolyl, an optionallysubstituted 3H-indazolyl, an optionally substituted indolizinyl, anoptionally substituted quinolinyl, an optionally substitutedisoquinolinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, anoptionally substituted benzothiazolyl, an optionally substitutedbenzoldlisoxazolyl, an optionally substituted benzoldlisothiazolyl, anoptionally substituted thiazolo[4,5-c]pyridinyl, an optionallysubstituted thiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pyridinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pyridinyl, an optionally substitutedoxazolo[5,4-b]pyridinyl, an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotriazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.

In another embodiment, in the compounds represented by formula (I), R₅is an optionally substituted indolyl. Preferably, R₅ is an indolylrepresented by the following structural formula:

wherein:

R₃₃ is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, alower haloalkoxy, and lower alkyl sulfanyl;

R₃₄ is H, a lower alkyl, or a lower alkylcarbonyl; and

Ring B and Ring C are optionally substituted with one or moresubstituents.

In another embodiment, in the compounds represented by formula (I), R₅is selected from the group consisting of:

wherein:

X₁₁, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(R₁₇),provided that at least one X₁₁ is N, N(O), or N⁺(R₁₇) and at least twoX₁₁ groups are independently selected from CH and CR₉;

X₁₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₂ group is independently selected from CHand CR₉;

X₁₃, for each occurrence, is independently O, S, S(O)p, NR₇, or NR₁₇;wherein R₇, R₉ and R₁₇ are defined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by formula (XII):

wherein R₁, R₃, and R₅ are defined as above; and

R₆, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and

n is zero of an integer from 1 to 4, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by structural formula (XIII):

wherein R₁, R₃, R₅, and R₆ are defined as above; and

R₂₅ is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH,—NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃,—OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇;

k is 1, 2, 3, or 4; and

r is zero or an integer from 1 to 3, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by structural formula (XIV):

wherein R₁, R₃, R₅, and R₂₅ are defined as above; and

R₁₂ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, cyano, halo, nitro, anoptionally substituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇, wherein R₇, R₈, R₁₀, R₁₁, and p are defined as above. Ina preferred embodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; R₁₂ is alower alkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉,for each occurrence, is independently selected from the group consistingof —OH, —SH, halo, a lower haloalkyl, cyano, a lower alkyl, a loweralkoxy, and a lower alkyl sulfanyl.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₃, R₅, R₆ and n are as defined above; and

X₃ and X₄ are each, independently, N, N(O), N⁺(R₁₇), CH or CR₆; and

X₅ is O, S, NR₁₇, CH═CH, CH═CR₆, CR₆═CH, CR₆═CR₆, CH═N, CR₆═N, CH═N(O),CR₆═N(O), N═CH, N═CR₆, N(O)═CH, N(O)═CR₆, N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₆,CH═N⁺(R₁₇), CR₆═N⁺(R₁₇), or N═N; wherein R₁₇ is defined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₃, R₅, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (II) asset forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein ring A, R₁ and R₃ are defined as above;and

R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith:

-   -   i) one substituent selected from nitro, cyano, a haloalkoxy, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,        guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,        —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or    -   ii) two to five substituents selected from the group consisting        of an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, an optionally substituted        heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,        nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,        —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;

R₂₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl;

p, for each occurrence, is, independently, 0, 1 or 2.

Compounds of formula (II) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (II) are particularlyuseful in treating cancer when given in combination with otheranti-cancer agent.

In one embodiment, the compounds represented by formula (II) do notinclude3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole,3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole,3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole,and 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by structural formula (XVIII):

wherein R₁, R₂, R₃, R₆, and n are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by structural formula (XIX):

wherein R₁, R₂, R₃, R₆, R₂₅ and r are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by structural formula (XX):

wherein R₁, R₂, R₃, R₁₂ and R₂₅ are defined as above. In a preferredembodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; R₁₂ is a lower alkyl,lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉, for eachoccurrence, is independently selected from the group consisting of —OH,—SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, anda lower alkyl sulfanyl.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₂, R₃, R₆, X₃, X₄, X₅ and n are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₂, R₃, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (III) asset forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs. In formula (III), ring A, R₁, and R₃ are defined as above;and

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

Compounds of formula (III) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (III) are particularlyuseful in treating cancer when given in combination with otheranti-cancer agent.

In one embodiment, in formula (III) R₁₈ is not cyclohexyl.

In another embodiment, in formula (III) R₁₈ is an optionally substitutedcycloalkyl or an optionally substituted cycloalkenyl.

In another embodiment, in formula (III) R₁₈ is a substituted alkyl.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by structural formula (XXIV):

wherein R₁, R₃, R₆, R₁₈, and n are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by structural formula (XXV):

wherein R₁, R₃, R₆, R₁₈, R₂₅ and r are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by structural formula (XXVI):

wherein R₁, R₃, R₁₂, R₁₈, and R₂₅ are defined as above. In a preferredembodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; and R₁₂ is a loweralkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₃, R₆, R₁₈, X₃, X₄, X₅, and n are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₃, R₁₈, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (IV) or(V) as set forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formulas (IV) and (V), R₁ and R₃ are as definedabove; and

X₁₄ is O, S, or NR₇;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

R₂₂, for each occurrence, is independently a substituent selected fromthe group consisting of H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, a

haloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently a substituentselected from the group consisting of H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

wherein R₇, R₈, R₁₀, R₁₁ and p are defined as above.

In one embodiment, in formulas (IV) and (V), R₂₁ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl.

In another embodiment, in the formulas (IV) and (V), R₁ is —OH, —SH, or—NHR₇.

In another embodiment, in the formulas (IV) and (V), R₂₂ is an alkyl, anaralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁.

In another embodiment, in the formulas (IV) and (V), X₁₄ is O.

Compounds of formula (IV) or (V) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (IV) or (V) areparticularly useful in treating cancer when given in combination withother anti-cancer agent.

In another embodiment, the invention provides compounds represented byformula (XXX):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁ is O, S, or NR₄₂;

X₄₂ is CR₄₄ or N;

Y₄₀ is N or CR₄₃;

Y₄₁ is N or CR₄₅;

Y₄₂, for each occurrence, is independently N, C or CR₄₆;

Z is OH, SH, or NHR₇;

R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₄₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;

R₄₃ and R₄₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heterocyclyl, oran optionally substituted heteroaryl;

R₄₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁;

R₄₆, for each occurrence, is independently selected from the groupconsisting of H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇, R₈, R₁₀, R₁₁, R₂₆, p, and m are defined as above.

In one embodiment, in formula (XXX), X₄₁ is NR₄₂ and X₄₂ is CR₄₄.

In another embodiment, in formula (XXX), X₄₁ is NR₄₂ and X₄₂ is N.

In another embodiment, in formula (XXX), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (XXX), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (XXX), X₄₁ is NR₄₂, and R₄₂ isselected from the group consisting of —H, a lower alkyl, a lowercycloalkyl, —C(O)N(R₂₇)₂, and —C(O)OH, wherein R₂₇, for each occurrence,is independently is —H or a lower alkyl.

In another embodiment, in formula (XXX), X₄₁ is NR₄₂, and R₄₂ isselected from the group consisting of —H, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂.

In one embodiment, Y₄₀ is CR₄₃. Preferably, Y₄₀ is CR₄₃ and R₄₃ is H ora lower alkyl.

In another embodiment, in formula (XXX), R₄₃ and R₄₄ are, independently,selected from the group consisting of —H, methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (XXX), X₄₂ is CR₄₄; Y is CR₄₃; and R₄₃and R₄₄ together with the carbon atoms to which they are attached form acycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspectof this embodiment, R₄₃ and R₄₄ together with the carbon atoms to whichthey are attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

In another embodiment, in formula (XXX), R₄₅ is selected from the groupconsisting of —H, —OH, —SH, —NH₂, a lower alkoxy, a lower alkyl amino,and a lower dialkyl amino.

In another embodiment, in formula (XXX), R₄₅ is selected from the groupconsisting of —H, —OH, methoxy and ethoxy.

In another embodiment, in formula (XXX), X₄₁ is O.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, in formula (XXX), Z is —OH.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, Z is —SH.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

Compounds of formula (XXX) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (XXX) are particularlyuseful in treating cancer when given in combination with otheranti-cancer agent.

In another aspect, the invention provides compounds represented byformula (XXXI):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

Z₁ is —OH or —SH;

X₄₂, R₄₁, R₄₂, R₄₃, and R₄₅ are defined as above.

In one embodiment, in formula (XXXI), Z₁ is —OH.

In another embodiment, in formula (XXXI), Z₁ is —SH.

In another embodiment, in formula (XXXI), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (XXXI), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (XXXI), R₄₂ is selected from the groupconsisting of lower alkyl, lower cycloalkyl, —C(O)N(R₂₇)₂, or —C(O)OH,wherein R₂₇, for each occurrence, is independently is —H or a loweralkyl.

In another embodiment, in formula (XXXI), R₄₂ is selected from the groupconsisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In another embodiment, R₄₃ is H or a lower alkyl.

In another embodiment, in formula (XXXI), X₄₂ is CR₄₄, and R₄₃ and R₄₄are, independently, selected from the group consisting of —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy.

In another embodiment, in formula (XXXI), X₄₂ is CR₄₄, and R₄₃ and R₄₄,taken together with the carbon atoms to which they are attached, form acycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Preferably, inthis embodiment, R₄₃ and R₄₄, taken together with the carbon atoms towhich they are attached, form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

In another embodiment, in formula (XXXI), R₄₅ is selected from the groupconsisting of —H, —OH, —SH, —NH₂, a lower alkoxy, a lower alkyl amino,and a lower dialkyl amino.

In another embodiment, in formula (XXXI), R₄₅ is selected from the groupconsisting of —H, —OH, methoxy, and ethoxy.

In another embodiment, in formula (XXXI), X₄₃ is CR₄₄.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononanlalindol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazoledisodium salt,

3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, in formula (XXXI), X₄₂ is N.

In another embodiment, the compound is selected from the groupconsisting of

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazoleHCL salt,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

Compounds of formula (XXXI) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (XXXI) areparticularly useful in treating cancer when given in combination withother anti-cancer agent.

In another aspect, the invention provides compounds represented byformula (XXXII):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₅ is CR₅₄ or N;

Z₁ is —OH or —SH;

R₅₂ is selected from the group consisting of —H, methyl, ethyl,n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH₂)₂OCH₃,—CH₂C(O)OH, and —C(O)N(CH₃)₂;

R₅₃ and R₅₄ are each, independently, —H, methyl, ethyl, or isopropyl; orR₅₃ and R₅₄ taken together with the carbon atoms to which they areattached form a phenyl, cyclohexenyl, or cyclooctenyl ring;

R₅₅ is selected from the group consisting of —H, —OH, —OCH₃, and—OCH₂CH₃; and

R₅₆ is selected from the group consisting of —H, methyl, ethyl,isopropyl, and cyclopropyl.

In one embodiment, in formula (XXXII), Z₁ is —OH.

In another embodiment, in formula (XXXII), Z₁ is —SH.

In another embodiment, in formula (XXXII), R₅₃ is H or a lower alkyl.

In another embodiment, in formula (XXXII), X₄₅ is CR₅₄. Preferably, R₅₄is H or a lower alkyl.

In another embodiment, X₄₅ is N.

In another embodiment, the compound is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole.

Compounds of formula (XXXII) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (XXXII) areparticularly useful in treating cancer when given in combination withother anti-cancer agent.

In another aspect, the invention provides compounds represented byformula (XXXIII):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein,

X₄₄, for each occurrence, is independently, O, NR₄₂ or C(R₄₆)₂;

Y₄₃ is NR₄₂ or C(R₄₆)₂;

Y₄₁, Y₄₂, Z, R₄₁, R₄₂, and R₄₆ are defined as above.

In one embodiment, in formula (XXXIII), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (XXXIII), R₄₁ is selected from thegroup consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (XXXIII), R₄₂ is selected from thegroup consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In another embodiment, in formula (XXXIII), Y₄₁ is CR₄₅. Preferably, R₄₅is H, a lower alkoxy, or —OH.

In another embodiment, in formula (XXXIII), Y₄₂ is CH.

In another embodiment, in formula (XXXIII), Y₄₃ is CH₂.

In another embodiment, in formula (XXXIII), Y₄₃ is NR₄₂, wherein R₄₂ isH or a lower alkyl.

In another embodiment, in formula (XXXIII), one of X₄₄ is NR₄₂ and theother is CH₂ or C(R₆)₂. Preferably, one of X₄₄ is NR₄₂ and the other isCH₂.

In another embodiment, in formula (XXXIII), Z is —OH.

In another embodiment, Z is —SH.

Compounds of formula (XXXIII) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (XXXIII) areparticularly useful in treating cancer when given in combination withother anti-cancer agent.

In another aspect, the invention provides compounds represented byformula (XXXIV):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁, Y₄₁, Y₄₂, Z, R₇, R₈, R₁₀, R₁₁, R₄₁, R₄₆, and p are defined asabove.

In one embodiment, in formula (XXXIV), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (XXXIV), R₄₁ is selected from thegroup consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (XXXIV), X₄₁ is NR₄₂. Preferably, R₄₂is selected from the group consisting of —H, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂. More preferably, R₄₂ is H or a lower alkyl.

In another embodiment, in formula (XXXIV), X₄₁ is O.

In another embodiment, in formula (XXXIV), X₄₁ is S.

In another embodiment, in formula (XXXIV), Y₄₁ is CR₄₅. Preferably, R₄₅is H, a lower alkoxy, or —OH.

In another embodiment, in formula (XXXIV), Y₄₂ is CH.

In another embodiment, in formula (XXXIV), R₄₆ is H or a lower alkyl.

In one embodiment, the compound is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole.

Compounds of formula (XXXIV) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of formula (XXXIV) areparticularly useful in treating cancer when given in combination withother anti-cancer agent.

In one embodiment the present invention provides compounds havingformula (I) as described above or a tautomer, pharmaceuticallyacceptable salt, solvate, clathrate or a prodrug thereof.

In another embodiment, the compounds of the present invention can berepresented by structural formula (XXXV):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

In formula (XXXV), R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆,—O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁, is —SHor —OH;

R₃ is —OH, —SH, —NR₇H, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈,—C(O)SH, —S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. In another embodiment, —OR₂₆ and —SR₂₆, are additionalvalues for R₃. Preferably, R₃ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. More preferably, R₃ is —OH, —SH, or —NHR₇. Even morepreferably, R₃ is —SH or —OH;

R₇₀ for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₇₀ for each occurrence, is independently anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇. More preferably, R₇₀ for each occurrence, isindependently a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. Even morepreferably, R₇₀ for each occurrence, is independently cyclopropyl orisopropyl;

R₇ and R₈, for each occurrence, is independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₇ and R₈, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₇ and R₈, for each occurrence, is independently —H or C1-C3alkyl.

R₁₀ and R₁₁, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₁₀ and R₁₁, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₁₀ and R₁₁, for each occurrence, is independently —H orC1-C3 alkyl.

Alternatively, R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl. Preferably R₁₀ and R₁₁, takentogether with the nitrogen to which they are attached, form anoptionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl,pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl,tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R₁₀ andR₁₁, taken together with the nitrogen to which they are attached, forman optionally substituted pyrrolidinyl, piperidinyl, piperazinyl,tetrahydroisoquinolinyl, morpholinyl or pyrazolyl.

R₇₁ for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably R₇₁ for each occurrence, is independently —OH,—SH, —NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃,—NHCH₃, —OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇. More preferably, R₇₁ for each occurrence, isindependently —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Evenmore preferably, R₇₁ for each occurrence, is independently —SH or —OH;

R₂₆ is a C1-C6 alkyl;

R₃₀ for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably R₃₀ for each occurrence, is independently anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇. More preferably, R₃₀ for each occurrence, isindependently a hydrogen, —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Evenmore preferably, R₃₀ for each occurrence, is independently a hydrogen,methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl;

R^(a) and R^(b), for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl or heteroaryl, an optionally substitutedaralkyl. Preferably, R^(a) and R^(b) for each occurrence, isindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl. More preferably, R^(a) andR^(b) for each occurrence, is independently a hydrogen, methyl, ethyl,propyl, isopropyl;

Alternatively, R^(a) and R^(b), taken together with the nitrogen towhich they are attached, form an optionally substituted heteroaryl orheterocyclyl. Preferably, R^(a) and R^(b) taken together with thenitrogen to which they are attached form a substituted or unsubstitutednonaromatic, nitrogen-containing heterocyclyl. More preferably, R^(a)and R^(b) taken together with the nitrogen to which they are attached,are:

k is 1, 2, 3 or 4;

p, for each occurrence, is independently, 0, 1 or 2;

m, for each occurrence, is independently, 1, 2, 3 or 4;

z and y for each occurrence, is independently an integer from 0 to 4.Preferably z and y for each occurrence, is independently 0, 1, or 2.More preferably z and y for each occurrence, is independently 0 or 1;and

x is 0 or 1, provided that z+x is less than or equal to 4.

In a first preferred embodiment, the values for the variables in formula(IV) are as described in the following paragraphs;

R₇₀, R₇₁ and R₃₀, for each occurrence, is independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₇₀ and R₃₀ are as just described and R₇₁ is—OH, —SH, —NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃,—SCH₃, —NHCH₃, —OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH,—SCH₂CH₂SH, —SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,—C(O)NR₁₀R₁₁, —C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, or —S(O)_(p)R₇;

k is 1, 2, 3, or 4;

z and y for each occurrence, is independently an integer from 0 to 4;

x is 0 or 1, provided that n+x less than or equal to 4; and

the values and preferred values for the remainder of the variables informula (IV) are as described immediately above.

In a second preferred embodiment, the present invention providescompounds represented by structural formula (XXXVI):

The values and preferred values for the variables in formula (XXXVI) areas described above for formula (XXXV). Alternatively, the values andpreferred values for the variables in formula (XXXVI) are as describedin the first preferred embodiment for formula (XXXV) immediately above.

In a third preferred embodiment, the present invention providescompounds represented by structural formula (XXXVII):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

The values and preferred values for the variables in formula (XXXVII)are as described above for formula (XXXV). Preferably, the values andpreferred values for the variables in formula (XXXVII) are as describedfor formula (XXXVI). More preferably, the values for the variables informula (XXXVII) are described in the following paragraphs:

R₃₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, cyano, halo, nitro, anoptionally substituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and the values and preferred values for the remainder ofthe variables are as described above for formula (XXXV). Preferably, thevalues and preferred values for the remainder of the variables informula (XXXVII) are as described for formula (XXXVI).

More preferably for formula (XXXVII), R₇₀ is an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl,haloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; the values for R₃₀ are as described in the precedingparagraph; and the values and preferred values for the remainder of thevariables are as described above for formula (XXXV). Preferably, thevalues and preferred values for the variables in formula (XXXVII) are asdescribed for formula (XXXVI).

In a fourth preferred embodiment, the present invention providescompounds represented by a structural formula selected from formulas(XXXVIII) and (XXXIX)

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

The values and preferred values for formulas (XXXVIII) and (XXXIX) areas described above for formula (XXXV). Preferably, the values andpreferred values for formulas (XXXVIII) and (XXXIX) are as describedabove for formula (XXXVII). More preferably, the values for thevariables in formulas (XXXVIII) and (XXXIX) are described in thefollowing paragraphs:

R₁, R₃ or R₇₁ are each independently —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. Preferably, R₁ and R₃ are each, independently, —OH, —SH,or —NHR₇ and R₇₁ is as just described; and

the values and preferred values for the remainder of the variables areas described above for formula (XXXV) or formula (XXXVII).

In a first more preferred embodiment for formulas (XXXVIII) and (XXXIX),R₁, R₃ and R₇₁ are as described in the immediately preceeding twoparagraphs: and

R^(a) and R^(b) are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; orR^(a) and R^(b) taken together with the nitrogen to which they areattached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and

the values and preferred values for the remainder of the variables areas described above for formula (XXXV) formula (XXXVII).

In a second more preferred embodiment for formulas (XXXVIII) and(XXXIX), R₇₀ is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, aC1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and thevalues and preferred values for the remainder of the variables are asdescribed above for first more preferred embodiment for formulas(XXXVIII) and (XXXIX).

In a third more preferred embodiment for formulas (XXXVIII) and (XXXIX):

R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇;

R₇₀ is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;

R₇₁ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂;

R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R₃₀ ismethyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

R^(a) and R^(b) are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; orR^(a) and R^(b) taken together with the nitrogen to which they areattached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and

the values and preferred values for the remainder of the variables areas described above for formula (XXXVII).

In a fourth more preferred embodiment for formulas (XXXVIII) and(XXXIX):

R₁, R₃ and R₇₁ for each occurrence, is independently —SH or —OH;

R₇₀ is cyclopropyl or isopropyl; and

the remainder of the variables are as described for the third morepreferred embodiment for formulas (XXXVIII) and (XXXIX). More preferablyR₃₀ is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. Even morepreferably, R₃₀ is methyl, ethyl, propyl, isopropyl, methoxy or ethoxyand R^(a) and R^(b) are each independently a hydrogen, methyl, ethyl,propyl, isopropyl, or taken together with the nitrogen to which they areattached, are:

wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl; and

the values and preferred values for the remainder of the variables areas described above for formula (XXXVII).

In another preferred embodiment, the present invention is a compoundrepresented by formula (XXXV), (XXXVI), (XXXVII), (XXXVIII) or (XXXIX),wherein R₁, R₃ and R₇₁ are —SH or —OH and R₆ is cyclopropyl or isopropyland the remainder of the variables are as described for Formula (XXXV),(XXXVI), (XXXVII), (XXXVIII) or (XXXIX), respectively.

In another embodiment, the present invention provides compoundsrepresented by a structural formula selected from formulas (XL) and(XLI):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

In formulas (XL) and (XLI), ring B is further optionally substitutedwith one or more substituents in addition to —NR^(a)R^(b). Preferablyring B is substituted with (R₃₀)_(y) where y is 0, 1, 2, 3 or 4,preferably y is 0 or 1;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁ is —SH or—OH;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₃ is —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₃ is —OH, —SH, or —NHR₇. Even more preferably, R₃ is —SH or—OH;

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇ or —SS(O)_(p)NR₁₀R₁₁. Preferably, R₇₀ is foreach occurrence, is independently an optionally substituted C1-C6 alkyl,an optionally substituted C3-C6 cycloalkyl, an optionally substitutedC3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, ahaloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl,—OH, —SH, —NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃,—SCH₃, —NHCH₃, —OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH,—SCH₂CH₂SH, —SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,—C(O)NR₁₀R₁₁, —C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —S(O)_(p)R₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₇₀, for each occurrence, is independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, —OH,—SH, —HNR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇,—SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇,—SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇,—OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Even more preferably, R₇₀ is for eachoccurrence, is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6cycloalkyl. Still more preferably, R₇₀ for each occurrence, isindependently a cyclopropyl or isopropyl;

R₇ and R₈, for each occurrence, is independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₇ and R₈, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₇ and R₈, for each occurrence, is independently —H or C1-C3alkyl;

R₁₀ and R₁₁, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₁₀ and R₁₁, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₁₀ and R₁₁, for each occurrence, is independently —H orC1-C3 alkyl;

alternatively, R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl. Preferably R₁₀ and R₁₁, takentogether with the nitrogen to which they are attached, form anoptionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl,pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl,tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R₁₀ andR₁₁, taken together with the nitrogen to which they are attached, forman optionally substituted pyrrolidinyl, piperidinyl, piperazinyl,tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;

R₁₇, for each occurrence, is independently an alkyl or an aralkyl.Preferably R₁₇ for each occurrence is independently a C1-C6 alkyl;

R₂₆ is a C1-C6 alkyl;

R₃₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—H, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, or —SS(O)_(p)NR₁₀R₁₁. Preferably R₃₀ foreach occurrence, is independently an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl,cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁ or—S(O)_(p)R₇. More preferably, R₃₀ for each occurrence, is independentlya hydrogen, —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl,C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Even morepreferably, R₃₀ for each occurrence, is independently a hydrogen,methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

R^(a) and R^(b), for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl or heteroaryl, an optionally substitutedaralkyl. Preferably, R^(a) and R^(b) for each occurrence, isindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl. More preferably, R^(a) andR^(b) for each occurrence, is independently a hydrogen, methyl, ethyl,propyl, isopropyl;

Alternatively, R^(a) and R^(b), taken together with the nitrogen towhich they are attached, form an optionally substituted heteroaryl orheterocyclyl. Preferably, R^(a) and R^(b) taken together with thenitrogen to which they are attached form a substituted or unsubstitutednonaromatic, nitrogen-containing heterocyclyl. More preferably, R^(a)and R^(b) taken together with the nitrogen to which they are attached,are:

X₃′ and X₄′ are each, independently, N, N(O), N⁺(R₁₇), CH or CR₇₀;

X₅′ is O, S, NR₁₇, CH₂, CH(R₇₀), C(R₇₀)₂, CH═CH, CH═CR₇₀, CR₇₀═CH,CR₇₀═CR₇₀, CH═N, CR₇₀═N, CH═N(O), CR₇₀═N(O), N═CH, N═CR₇₀, N(O)═CH,N(O)═CR₇₀, N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₇₀, CH═N⁺(R₁₇), CR₇₀═N⁺(R₁₇), or N═N,provided that at least one X₃′, X₄′ or X₅′ is a heteroatom;

k is 1, 2, 3, or 4;

p, for each occurrence, is independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In a fifth preferred embodiment, the present invention provides acompound represented by a structural formula selected from formulas(XLII) and (XLIII):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

Preferably the values and preferred values for formulas (XLII) and(XLIII) are as described above for formulas (XL) and (XLI), and morepreferably:

R₇₀ is for each occurrence, is independently an optionally substitutedC1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionallysubstituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl,a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, analkylsulfanyl, —OH, —SH, —NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH,—(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃, —OCH₂CH₂OH, —OCH₂CH₂SH,—OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH, —SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇,—OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—S(O)_(p)R₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂;

R₃₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇ or —SS(O)_(p)NR₁₀R₁₁;

s is 0, 1, 2, 3 or 4;

k is 1, 2, 3, or 4; and

the values and preferred values for the remainder of the variables areas described above for formulas (XL) and (XLI).

In a sixth preferred embodiment, the present invention provides acompound represented by a structural formula selected from formulas(XLIV) and (XLV):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

The values and preferred values for formulas (XLIV) and (XLV) are asdescribed above for formulas (XL) and (XLI). Preferably the values andpreferred values for formulas (XLIV) and (XLV) are as described forformulas (XLII) and (XLIII). More preferably, the values for formulas(XLIV) and (XLV) are described in the following paragraphs:

R₃₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, cyano, halo, nitro, anoptionally substituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and

the values and preferred values for the remainder of the variables areas described above for formulas (XLIV) and (XLV) are as described abovefor formulas (XL) and (XLI). Preferably the values and preferred valuesfor the remainder of the variables in formulas (XLIV) and (XLV) are asdescribed for formulas (XLII) and (XLIII).

In a seventh more preferred embodiment, the present invention provides acompound represented by a structural formula selected from formulas(XLVI)-(XLIX):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

The values and preferred values for formulas (XLVI)-(XLIX) are asdescribed above for formulas (XL) and (XLI). Preferably the values andpreferred values for formulas (XLVI)-(XLIX) are as described above forformulas (XLIV) and (XLV). More preferably, the values for formulas(XLVI)-(XLIX) are provided below in the following paragraphs:

R₁ and R₃ are each independently —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂; and

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂; and

the values and preferred values for the remainder of the variables areas described for formulas (XLIV) and (XLV).

Still more preferably for formulas (XLVI)-(XLIX), R₁, R₃ and R₇₀ are asdescribed in the immediately preceeding paragraphs; and

R^(a) and R^(b) are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; orR^(a) and R^(b) taken together with the nitrogen to which they areattached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and

the values and preferred values for the remainder of the variables areas described for formulas (XLIV) and (XLV).

Still more preferably for formulas (XLVI)-(XLIX), R₁, R₃, R₆, R^(a) andR^(b) are as described in the immediately preceeding paragraphs; and

R₇₀ is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and

the values and preferred values for the remainder of the variables areas described above for formulas (XL) and (XLI). More preferably, thevalues and preferred values for the remainder of the variables are asdescribed above for formulas (XLIV) and (XLV).

In an eighth preferred embodiment, the present invention provides acompound represented by a structural formula selected from formulas(La)-(Lp):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof.

The values and preferred values for formulas (La) through (Lp) are asdescribed above for formulas (XL) and (XLI). Preferably the values andpreferred values for formulas (La)-(Lp) are as described for formulas(XLVI)-(XLIX). More preferably, R₁ and R₃ are each, independently, —OH,—SH, or —NHR₇. Even more preferable, R₁ and R₃ are each, independently,—OH, —SH, or —NHR₇; and R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl(preferably methyl, ethyl, propyl, isopropyl, methoxy or ethoxy). Evenmore preferably, R₁ and R₃ for each occurrence, is independently —SH or—OH; R₇₀ is cyclopropyl or isopropyl; and R₃₀ is —OH, —SH, halogen,cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy orC1-C6 alkyl sulfanyl (preferably methyl, ethyl, propyl, isopropyl,methoxy or ethoxy). Even more preferably yet, R₁, R₃, R₇₀ and R₃₀ are asjust described and R^(a) and R^(b) are each independently a hydrogen,methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen towhich they are attached, are:

R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl; and

the values and preferred values for the remainder of the variables areas defined for formulas (XLVI)-(XLIX).

In another embodiment the compounds of the present invention arerepresented by a structural formula selected from formulas (LIa) and(LIb):

-   -   or a tautomer, pharmaceutically acceptable salt, solvate,        clathrate or a prodrug thereof.

In formulas (LIa) and (LIb), ring B is further optionally substitutedwith one or more substituents in addition to —NR^(a)R^(b). Preferablyring B is further substituted with (R₃₀)_(s) where s is 0, 1, 2, 3 or 4,preferably s is 0 or 1;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —S C(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁ is —SH or—OH;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₃ is —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₃ is —OH, —SH, or —NHR₇. Even more preferably, R₃ is —SH or—OH;

R₇ and R₈, for each occurrence, is independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₇ and R₈, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₇ and R₈, for each occurrence, is independently —H or C1-C3alkyl;

R₁₀ and R₁₁, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl. Preferably, R₁₀ and R₁₁, for each occurrence, isindependently —H, C1-C3 alkyl, C1-C6 cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Morepreferably, R₁₀ and R₁₁, for each occurrence, is independently —H orC1-C3 alkyl;

Alternatively, R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl. Preferably R₁₀ and R₁₁, takentogether with the nitrogen to which they are attached, form anoptionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl,pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl,tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably R₁₀ andR₁₁, taken together with the nitrogen to which they are attached, forman optionally substituted pyrrolidinyl, piperidinyl, piperazinyl,tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;

R₂₂, for each occurrence, is independently —H, an optionally substitutedalky, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteroaralkyl, ahaloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁. Preferably, R₂₂ is —H,an alkyl, an aralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁;

R₂₃ and R₂₄, for each occurrence, is independently —H, an optionallysubstituted alky, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁. Preferably, R₂₃ and R₂₄ for eachoccurrence is independently —H;

R₂₆ is a C1-C6 alkyl;

R^(a) and R^(b), for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl or heteroaryl, an optionally substitutedaralkyl. Preferably, R^(a) and R^(b) for each occurrence, isindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl. More preferably, R^(a) andR^(b) for each occurrence, is independently a hydrogen, methyl, ethyl,propyl or isopropyl;

Alternatively, R^(a) and R^(b), taken together with the nitrogen towhich they are attached, form an optionally substituted heteroaryl orheterocyclyl. Preferably, R^(a) and R^(b) taken together with thenitrogen to which they are attached form a substituted or unsubstitutednonaromatic, nitrogen-containing heterocyclyl. More preferably, R^(a)and R^(b) taken together with the nitrogen to which they are attached,are:

X₁₄ is O, S, or NR₇. Preferably, X₁₄ is O;

p, for each occurrence, is independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

Preferably for the compound represented by formulas (LIa) and (LIb), R₁is —OH, —SH, or —NHR₇; and R₂₂ is —H, an alkyl, an aralkyl, —C(O)R₇,—C(O)OR₇, or —C(O)NR₁₀R₁₁. More preferably, R₁ is —OH, —SH, or —NHR₇;R₂₂ is —H, an alkyl, an aralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; andX₁₄ is O. The values and preferred values for the remainder of thevariables are as described above.

In one embodiment, a compound of the present invention is represented bythe structural formulas (VI)-(VIII):

In formulas (VI-VIII):

ring A is an aryl or a heteroaryl, optionally further substituted withone or more substituents in addition to R₃. Preferably, Ring A isrepresented one of the following structural formulas:

where z is 0, 1, 2, 3 or 4; x is 0 or 1; and z+x is less than or equalto 4.

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁, is —SHor —OH;

R₂′ is an optionally substituted phenyl group. Preferably, R₂′ issubstituted with one or more group represented by R₃₀, wherein R₃₀, foreach occurrence, are independently an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. More preferably, R₂′ is an optionally substituted indolylgroup or a phenyl group substituted with NR₁₀R₁₁ and optionally with atleast one other substitutent represented by R₃₀;

R₃ is —OH, —SH, —NR₇H, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈,—C(O)SH, —S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. In another embodiment, —OR₂₆ and —SR₂₆, are additionalvalues for R₃. Preferably, R₃ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. More preferably, R₃ is —OH, —SH, or —NHR₇. Even morepreferably, R₃ is —SH or —OH;

R₅ is an optionally substituted heteroaryl; an optionally substituted 6to 14-membered aryl.

R₇₀, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. Preferably, R₇₀ is selected from thegroup consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, andC1-C6 cycloalkoxy, more preferably from the group consisting of —H,methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,and cyclopropoxy.

R₇₁, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂.

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

R₅ in structural formula (VI) is preferably represented by the followingstructural formula:

wherein:

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and

m is zero or an integer from 1 to 7.

More preferably, substituent R₅ in structural formula (VI) isrepresented by one of the following structural formulas:

wherein:

R₉ is as defined as above, q is zero or an integer from 1 to 7 and u iszero or an integer from 1 to 8.

In another alternative, R₅ in structural formula (VI) is represented bythe following structural formula:

wherein:

R₃₃ is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, alower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl, ora lower alkylcarbonyl; and ring B and ring C are optionally substitutedwith one or more substituents.

In another alternative, R₅ in structural formula (VI) is selected from agroup listed in Table 1.

TABLE 1 # R₅ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

In the structural formulas of Table 1:

X₆, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₆ groups are independently selected fromCH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₇ groups are independently selected fromCH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, CR₉R₉, O, S,S(O)_(p), NR₇, or NR₁₇;

X₉, for each occurrence, is independently N or CH;

X₁₀, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₀ is selected from CH and CR₉;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and

R₁₇, for each occurrence, is independently —H, an alkyl, an aralkyl,—C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁.

Preferred R₅ groups from Table 1 are selected from the group consistingof an optionally substituted indolyl, an optionally substitutedbenzoimidazolyl, an optionally substituted indazolyl, an optionallysubstituted 3H-indazolyl, an optionally substituted indolizinyl, anoptionally substituted quinolinyl, an optionally substitutedisoquinolinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, anoptionally substituted benzothiazolyl, an optionally substitutedbenzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, anoptionally substituted thiazolo[4,5-c]pylidinyl, an optionallysubstituted thiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pylidinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pylidinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pylidinyl, an optionally substitutedoxazolo[5,4-b]pylidinyl, an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotnazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.

In another alternative, R₅ in structural formula (VI) is selected fromthe group consisting of:

wherein:

X₁₁, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(R₁₇),provided that at least one X₁₁ is N, N(O), or N⁺(R₁₇) and at least twoX₁₁ groups are independently selected from CH and CR₉;

X₁₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₂ group is independently selected from CHand CR₉;

X₁₃, for each occurrence, is independently O, S, S(O)_(p), NR₇, or NR₁₇;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and R₁₇, for eachoccurrence, is independently an alkyl or an aralkyl. The remainder ofthe variables have values defined above with reference to structuralformula (I).

In a preferred embodiment, the compound of the invention is representedby structural formula (LII):

In structural formula (LII):

X₁₀₁ is O, S, or NR₁₀₂ and X₁₀₂ is CR₁₀₄ or N. Preferably, X₁₀₁ is NR₁₀₂and X₁₀₂ is CR₁₀₄. Alternatively, X₁₀₁ is NR₁₀₂ and X₁₀₂ is N;

Y, for each occurrence, is independently N or CR₁₀₃;

Y₁₀₁ is N or CR₁₀₅;

Y₁₀₂ is N, C or CR₁₀₆;

R₁ is —OH, —SH, or NHR₇. Preferably, R₁ is —OH or —SH;

R₇₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, an alkoxy, cycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇,—OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇,—SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇,—NR₇C(O)OR₇, —NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁,—NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇,—OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇,—SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. Preferably, R₇₀ isselected from the group consisting of —H, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 cycloalkyl, and C1-C6 cycloalkoxy, more preferably from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy;

R₁₀₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;preferably, R₁₀₂ is selected from the group consisting of —H, a C1-C6alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂, and —C(O)OH, wherein R₂₇, foreach occurrence, is independently is —H or a lower alkyl;

R₁₀₃ and R₁₀₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₁₀₃ and R₁₀₄ taken together with the carbon atomsto which they are attached form an optionally substituted cycloalkenyl,an optionally substituted aryl, an optionally substituted heterocyclyl,or an optionally substituted heteroaryl; preferably, R₁₀₃ and R₁₀₄ areindependently, selected from the group consisting of —H, methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy;

R₁₀₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; preferably, R₁₀₅is selected from the group consisting of —H, —OH, —SH, —NH₂, a C1-C6alkoxy, a C1-C6 alkyl amino, and a C1-C6 dialkyl amino, more preferablyfrom the group consisting of —H, —OH, methoxy and ethoxy; and

R₁₀₆, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

The remainder of the variables of the compounds of structural formula(LII) has values defined above with reference to structural formula(VI).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (LII), X₁₀₁ is NR₁₀₂, R₁₀₂ is selected from thegroup consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂,and —C(O)OH, each R₂₇, for each occurrence, is independently is —H or alower alkyl, and the values for the remainder of the variables are asdescribed above for formula (LII).

In a second preferred set of values for the variables of the Hsp90inhibitor represented by formula (LII), X₁₀₁ is NR₁₀₂, R₁₀₂ is selectedfrom the group consisting of —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂ and the valuesfor the remainder of the variables are as described above for formula(LII).

In third preferred set of values for the variables of the Hsp90inhibitor represented by formula (LII), X₁₀₂ is CR₁₀₄; Y is CR₁₀₃; andR₁₀₃ and R₁₀₄ together with the carbon atoms to which they are attachedform a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.Preferably, R₁₀₃ and R₁₀₄ together with the carbon atoms to which theyare attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl and the valuesfor the remainder of the variables are as described above for formula(LII).

In fourth preferred set of values for the variables of the Hsp90inhibitor represented by formula (LII), R₁ is —OH or —SH and the valuesfor the remainder of the variables are as described above for formula(LII).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by structural formula (LIII):

where X₁₀₃ is CR₁₀₄ or N and the remainder of the variables is definedabove with reference with structural formulas (LII).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by a structural formula selected from formulas(LIVa)-(LIVi):

The values for the variables in structural formulas (LIVa)-(LIVi) are asdescribed in structural formulas (VI), (VII), and (VIII).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by structural formulas (LIVa)-(LIVi):

R₅ is as described for structural formula (VI), (VII), and (VIII) or astructural formula from Table 1;

R₇₀ and R₇₁, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

z in structural formula (LIVa)-(LIVc) is zero or an integer from 1 to 4;z in structural formula (LIVd)-(LIVf) is zero or an integer from 1 to 3;

x is 0 or 1;

z+x in structural formula (LIVa)-(LIVc) is less than or equal to 4; and

the remainder of the variables in formulas (LIVa)-(LIVi) have valuesdefined above with reference to structural formula (VI), (VII) and(VIII).

A second preferred set of values for the variables of the Hsp90inhibitor represented by structural formula (LIVa)-(LIVc) is provided inthe following paragraphs:

R₇₁ is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH,—NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃,—OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and k is 1, 2, 3, or 4; and R₁, R₃, R₇₀ and theremainder of the variables are as described in the first preferred setof values for the variables in structural formulas (LIVa)-(LIVc).Preferably, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

A third preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (LIVa)-(LIVc) is provided in the followingparagraphs:

R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇;

R₇₀ is an optionally substituted alkyl or cycloalkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, cyano, halo,nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy,haloalkoxy, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₁ and R₃ and the remainder of the variables are asdescribed in the second preferred set of values for the variables instructural formulas (LIVa)-(LIVc).

In a fourth preferred set of values for the variables of StructuralFormulas (LIVa)-(LIVc):

R₁ is —SH or —OH;

R₃ and R₇₁ are —OH;

R₇₀ is a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl, or —NR₁₀R₁₁; and

The remainder of the variables are as defined in Structural Formula(VI)-(VIII).

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from formulas (LVa)-(LVf):

In formulas (LVa) and (LVb):

R₅ is as described for structural formula (VI) or a structural formulafrom Table 1;

X₃′ and X₄′ are each, independently, N, N(O), N⁺(R₁₇), CH or CR₇₀;

X₅′ is O, S, NR₁₇, CH₂, CH(R₇₀), C(R₇₀)₂, CH═CH, CH═CR₇₀, CR₇₀═CH,CR₇₀═CR₇₀, CH═N, CR₇₀═N, CH═N(O), CR₇₀═N(O), N═CH, N═CR₇₀, N(O)═CH,N(O)═CR₇₀, N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₇₀, CH═N⁺(R₁₇), CR₇₀═N⁺(R₁₇), or N═N,provided that at least one X₃′, X₄′ or X₅′ is a heteroatom;

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₁₇, for each occurrence, is independently an alkyl or an aralkyl; and nis zero or an integer from 1 to 4; and

the remainder of the variables has values defined above with referenceto structural formulas (VI), (VII), and (VIII).

Preferably, Hsp90 inhibitor of structural formulas (LVa)-(LVf) areselected from Table 2a-c.

TABLE 2a Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

TABLE 2b Number Compound 1

2

3

4

5

6

7

8

9

10

TABLE 2c Number Compound 1

2

3

4

5

6

7

8

9

10

The values for the variables for the formulas in Tables 2a-c are asdefined for structural formulas (LVa)-(LVf). Preferably, R₇₀ is a halo,a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR₇, —(CH₂)_(k)OH,—(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃, —OCH₂CH₂OH,—OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH, —SCH₂CH₂NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and

k is 1, 2, 3, or 4.

In another preferred embodiment, the Hsp90 inhibitor of the presentinvention is represented by structural formula (LVI):

R₇₀ and R₇₁, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₇₀ is selected from an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl,haloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₇₁ is as just described. The values for theremainder of the variables are as described for structural formulas(VI), (VII), and (VIII).

In another preferred embodiment, the Hsp90 inhibitors is represented bystructural formula (LVIIa) or (LVIIb):

The variables in formulas (LVIIa) and (LVIIb) are defined above withreference to formula (LVI).

A first preferred set of values for the variables of structural formula(LVIIa) and (LVIIb) is provided in the following paragraph:

R₁, R₃ or R₇₁ are each independently selected from —OH, —SH, —NHR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂, and p, R₇₀, R₇, R₈, R₁₀, R₁₁ and R₃₀ are as described forstructural formula (LVI). Preferably, when R₁, R₃ and R₇₁ have thesevalues, R₁₀ and R₁₁ are preferably each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and p, R₇₀, R₇, and R₃₀ are asdescribed for structural formula (LVI). More preferably, when R₁, R₃,R₁₀, R₁₁, and R₇₁ have these values, R₇₀ is preferably a C1-C6 alkyl, aC1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl; and p, R₇, R₈ and R₃₀ are as describedfor structural formula (LVI).

A second preferred set of values for the variables of structural formula(LVIIa) and (LVIIb) is provided in the following paragraph:

R₁ and R₃ are each independently —OH or —SH; R₇₀ is preferably a C1-C6alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6alkyl sulfanyl or a C3-C6 cycloalkyl; R₁₀ and R₁₁ are preferably eachindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl; or R₁₀ and R₁₁ taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted nonaromatic, nitrogen-containing heterocyclyl; R₇₁ is —OH,—SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇,—SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇,—SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇,—OP(O)(OR₇)₂ or —SP(O)(OR₇)₂; and p, R₇ R₈ and R₃₀ are as described forstructural formula (LVI). Preferably, R₃₀ is a —OH, —SH, halogen, cyano,a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl and the remainder of the variables are as just described.

A third preferred set of values for the variables of structural formula(LVIIa) and (LVIIb) is provided in the following paragraph:

R₁, R₃ and R₇₁ are independently —SH or —OH; R₇₀ is cyclopropyl orisopropyl; R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6straight or branched alkyl, optionally substituted by —OH, —CN, —SH,amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and R₃₀ is —OH, —SH, halogen, cyano, aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl. Preferably, R₃₀ is a methyl, ethyl, propyl, isopropyl,methoxy or ethoxy. More preferably, R₁, R₃, R₇₀, R₇₁ and R₃₀ are as justdescribed and R₁₀ and R₁₁ are each independently a hydrogen, methyl,ethyl, propyl, isopropyl, or taken together with the nitrogen to whichthey are attached, are:

wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another preferred embodiment, the Hsp90 inhibitor is represented bystructural formulas (LVIIIa) or (LVIIIb):

The values for the variables in structural formulas (LVIIIa) and(LVIIIb) are as described for structural formulas (LVc) and (LVd).Preferably, R₃₀ is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇,—OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇,—SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇,—NR₇C(O)OR₇, —NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁,—NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇,—OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇,—SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. More preferably, R₃₀is an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇.

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from formulas (LIXa)-(LIXd):

The values of the variables in structural formulas (LIXa)-(LIXd) aredefined above with reference to structural formulas (LVIIIa) and(LVIIIb).

A first preferred set of values for the variables in structural formulas(LIXa)-(LIXd) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH or —SH, —HNR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂;

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. Preferably, R₇₀ is a C1-C6 alkyl, a C1-C6 haloalkyl, aC1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6cycloalkyl; and

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(LIXa)-(LIXd) are as described for structural formulas (LVIIIa) and(LVIIIb). Preferably, R₁₀ and R₁₁ are each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl.

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from formulas (LXa)-(LXp):

The values of the variables in structural formulas (LXa)-(LXp) aredefined above with reference to structural formulas (XIXa)-(XIXd).

A first preferred set of values for the variables in structural formulas(LX) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH or —SH, or —HNR₇;

R₇₀, is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(LXa)-(LXp) are as described for structural formulas (LVIIIa) and(LVIIIb). Preferably, R₁₀ and R₁₁ are each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and

R₃₀ and the remainder of the variables in structural formulas(LXa)-(LXp) are as described for structural formulas (LIXa)-(LIXd).Preferably, R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.

A second preferred set of values for the variables in structuralformulas (LXa)-(LXp) are as described in the following paragraphs:

R₁ and R₃ are independently —SH or —OH;

R₇₀ is cyclopropyl or isopropyl;

R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R₁₀and R₁₁ taken together with the nitrogen to which they are attached forma substituted or unsubstituted nonaromatic, nitrogen-containingheterocyclyl;

R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R₃₀ is amethyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainderof the variables are as described for formulas (LVIIIa) and (LVIIIb).More preferably, R₁₀ and R₁₁ are each independently a hydrogen, methyl,ethyl, propyl, isopropyl, or taken together with the nitrogen to whichthey are attached, are:

-   -   wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another embodiment, the Hsp90 inhibitor of the present invention isrepresented by structural formulas (LXIa) or (LXIb):

In formulas (LXIa) and (LXIb):

X₁₄ is O, S, or NR₇. Preferably, X₁₄ is O;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, or —NHR₇;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl. Preferably, R₂₁ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Alternatively,R₂₁ is

wherein

R₁₀ and R₁₁ is defined as above; and

R₃₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

z and q are independently an integer from 0 to 4; and

x is 0 or 1, provided that z+x less than or equal to 4.

R₂₂, for each occurrence, is independently a substituent selected fromthe group consisting of H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, ahaloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁. Preferably, R₂₂ is analkyl, an aralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently a substituentselected from the group consisting of H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In one embodiment, a compound of the present invention is represented bya structural formula selected from formulas (IX), (X) and (XI):

In formulas (IX)-(XI):

ring A is an aryl or a heteroaryl, optionally further substituted withone or more substituents in addition to R₃. Preferably, Ring A isrepresented one of the following structural formulas:

wherein z is 0, 1, 2, 3 or 4; x is 0 or 1; and z+x is less than or equalto 4.

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁, is —SHor —OH;

R₂′ is an optionally substituted phenyl group. Preferably, R₂′ issubstituted with one or more group represented by R₃₀, wherein R₃₀, foreach occurrence, are independently an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. More preferably, R₂′ is an optionally substituted indolylgroup or a phenyl group substituted with NR₁₀R₁₁ and optionally with atleast one other substitutent represented by R₃₀;

R₃ is —OH, —SH, —NR₇H, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈,—C(O)SH, —S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. In another embodiment, —OR₂₆ and —SR₂₆, are additionalvalues for R₃. Preferably, R₃ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. More preferably, R₃ is —OH, —SH, or —NHR₇. Even morepreferably, R₃ is —SH or —OH.

R₅ is an optionally substituted heteroaryl; an optionally substituted 6to 14-membered aryl.

R₇₀, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. Preferably, R₇₀ is selected from thegroup consisting of —H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, andC1-C6 cycloalkoxy, more preferably from the group consisting of —H,methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,and cyclopropoxy.

R₇₁, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂.

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

R₅ in structural formula (IX) is preferably represented by the followingstructural formula:

wherein:

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring, and m is zero or aninteger from 1 to 7. More preferably, substituent R₅ is represented byone of the following structural formulas:

wherein:

R₉ is as defined as above; q is zero or an integer from 1 to 7; and u iszero or an integer from 1 to 8. The remainder of the variables havevalues defined above with reference to structural formula (IX).

In another alternative, R₅ in structural formula (IX) is represented bythe following structural formula:

wherein:

R₃₃ is —H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, alower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl, ora lower alkylcarbonyl; and ring B and ring C are optionally substitutedwith one or more substituents. The remainder of the variables havevalues defined above with reference to structural formula (IX).

In another alternative, R₅ in structural formula (IX) is selected from agroup listed in Table 3.

TABLE 3 Number Substituent R₅ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

In the structural formulas of Table 3:

X₆, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₆ groups are independently selected fromCH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₇ groups are independently selected fromCH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, CR₉R₉, O, S, S(O)p,NR₇, or NR₁₇;

X₉, for each occurrence, is independently N or CH;

X₁₀, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₀ is selected from CH and CR₉;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and

R₁₇, for each occurrence, is independently —H, an alkyl, an aralkyl,—C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁.

Preferred R₅ groups from Table 3 are selected from the group consistingof an optionally substituted indolyl, an optionally substitutedbenzoimidazolyl, an optionally substituted indazolyl, an optionallysubstituted 3H-indazolyl, an optionally substituted indolizinyl, anoptionally substituted quinolinyl, an optionally substitutedisoquinolinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, anoptionally substituted benzothiazolyl, an optionally substitutedbenzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, anoptionally substituted thiazolo[4,5-c]pylidinyl, an optionallysubstituted thiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pylidinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pylidinyl, an optionally substitutedoxazolo[5,4-b]pylidinyl, an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotnazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pylimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.

In another alternative, R₅ in structural formula (IX) is selected fromthe group consisting of:

wherein:

X₁₁, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(R₁₇),provided that at least one X₁₁ is N, N(O), or N⁺(R₁₇) and at least twoX₁₁ groups are independently selected from CH and CR₉;

X₁₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₂ group is independently selected from CHand CR₉;

X₁₃, for each occurrence, is independently O, S, S(O)p, NR₇, or NR₁₇;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and R₁₇, for eachoccurrence, is independently an alkyl or an aralkyl. The remainder ofthe variables have values defined above with reference to structuralformula (IX).

In a preferred embodiment, the compound of the invention is representedby structural formula (LXII):

In structural formula (LXII):

X₁₀₁ is O, S, or NR₁₀₂ and X₁₀₂ is CR₁₀₄ or N. Preferably, X₁₀₁ is NR₁₀₂and X₁₀₂ is CR₁₀₄. Alternatively, X₁₀₁ is NR₁₀₂ and X₁₀₂ is N;

Y, for each occurrence, is independently N or CR₁₀₃;

Y₁₀₁ is N or CR₁₀₅;

Y₁₀₂ is N, C or CR₁₀₆;

R₁ is OH, SH, or NHR₇. Preferably, R₁ is —OH or —SH;

R₇₀ is —H, —OH, —SH, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₇₀ is selected from the group consisting of—H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy,more preferably from the group consisting of —H, methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;

R₁₀₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;preferably, R₁₀₂ is selected from the group consisting of —H, a C1-C6alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂, and —C(O)OH, wherein R₂₇, foreach occurrence, is independently is —H or a lower alkyl;

R₁₀₃ and R₁₀₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₁₀₃ and R₁₀₄ taken together with the carbon atomsto which they are attached form an optionally substituted cycloalkenyl,an optionally substituted aryl, an optionally substituted heterocyclyl,or an optionally substituted heteroaryl; preferably, R₁₀₃ and R₁₀₄ areindependently, selected from the group consisting of —H, methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy;

R₁₀₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; preferably, R₁₀₅is selected from the group consisting of —H, —OH, —SH, —NH₂, a C1-C6alkoxy, a C1-C6 alkyl amino, and a C1-C6 dialkyl amino, more preferablyfrom the group consisting of —H, —OH, methoxy and ethoxy; and

R₁₀₆, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

The remainder of the variables of the compounds of structural formula(LXII) has values defined above with reference to structural formula(IX).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (LXII), X₁₀₁ is NR₁₀₂, R₁₀₂ is selected from thegroup consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂,and —C(O)OH, wherein R₂₇, for each occurrence, is independently is —H ora lower alkyl and the values for the remainder of the variables are asdescribed above for formula (LXII).

In a second preferred set of values for the variables of the Hsp90inhibitor represented by formula (LXII), X₁₀₁ is NR₁₀₂, R₁₀₂ is selectedfrom the group consisting of —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂ and the valuesfor the remainder of the variables are as described above for formula(LXII).

In third preferred set of values for the variables of the Hsp90inhibitor represented by formula (LXII), X₁₀₂ is CR₁₀₄; Y is CR₁₀₃; andR₁₀₃ and R₁₀₄ together with the carbon atoms to which they are attachedform a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.Preferably, R₁₀₃ and R₁₀₄ together with the carbon atoms to which theyare attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl and the valuesfor the remainder of the variables are as described above for formula(LXII).

In fourth preferred set of values for the variables of the Hsp90inhibitor represented by formula (LXII), R₁ is —OH or —SH and the valuesfor the remainder of the variables are as described above for formula(LXII).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by structural formula (LXIII):

where X₁₀₃ is CR₁₀₄ or N and the remainder of the variables is definedabove with reference with structural formulas (LXII).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by structural formula selected from (LXIVa)-(LXIVi):

The values for the variables in structural formulas (LXIVa)-(LXIVi) areas described in structural formula (IX), (X), and (XI).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by structural formulas (VIa-c)-(VIIIa-c):

R₅ is as described for structural formula (IX), (LXII), (LXIII) or astructural formula from Table 1;

R₇₀ and R₇₁, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₇)R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

z in structural formula (VIa-c) is zero or an integer from 1 to 4; z instructural formula (VIIa-c) is zero or an integer from 1 to 3;

x is 0 or 1;

z+x in structural formula (LXIVa)-(LXIVc) is less than or equal to 4;and

the remainder of the variables in formulas (LXIVa)-(LXIVi) have valuesdefined above with reference to structural formula (IX), (X), and (XI).

A second preferred set of values for the variables of the Hsp90inhibitor represented by structural formula (LXIVa)-(LXIVi) is providedin the following paragraphs:

R₇₁ is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH,—NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃,—OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and k is 1, 2, 3, or 4; and R₁, R₃, R₇₀ and theremainder of the variables are as described in the first preferred setof values for the variables in structural formulas (LXIVa)-(LXIVi).Preferably, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

A third preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (LXIVa)-(LXIVi) is provided in the followingparagraphs:

R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇;

R₇₀ is an optionally substituted alkyl or cycloalkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, cyano, halo,nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy,haloalkoxy, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₁ and R₃ and the remainder of the variables are asdescribed in the second preferred set of values for the variables instructural formulas (LXIVa)-(LXIVi).

In a fourth preferred set of values for the variables of StructuralFormulas (LXIVa)-(LXIVi):

R₁ is —SH or —OH;

R₃ and R₂₅ are —OH;

R₇₀ is a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl, or —NR₁₀R₁₁; and

The remainder of the variables are as defined in Structural Formula(IX), (X), and (XI).

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from (LXVa)-LXVf):

In formulas (LXVa) and (LXVb):

R₅ is as described for structural formula (IX), (LXII), or (LXIII), or astructural formula from Table 1;

X₃′ and X₄′ are each, independently, N, N(O), N⁺(R₁₇), CH or CR₇₀;

X₅′ is O, S, NR₁₇, CH₂, CH(R₇₀), C(R₇₀)₂, CH═CH, CH═CR₇₀, CR₇₀═CH,CR₇₀═CR₇₀, CH═N, CR₇₀═N, CH═N(O), CR₇₀═N(O), N═CH, N═CR₇₀, N(O)═CH,N(O)═CR₇₀, N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₇₀, CH═N⁺(R₁₇), CR₆₀═N⁺(R₁₇), or N═N,provided that at least one X₃′, X₄′ or X₅′ is a heteroatom;

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₁₇, for each occurrence, is independently an alkyl or an aralkyl; and nis zero or an integer from 1 to 4; and

the remainder of the variables has values defined above with referenceto structural formulas (IX), (X), and (XI).

Preferably, Hsp90 inhibitor of structural formulas (LXVa)-LXVf) areselected from Table 4a-c.

TABLE 4a Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

TABLE 4b Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

TABLE 4c Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

The values for the variables for the formulas in Tables 4a-c are asdefined for structural formulas (LXVa)-(LXVf). Preferably, R₇₀ is ahalo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR₇,—(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃,—OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and

k is 1, 2, 3, or 4.

In another preferred embodiment, the Hsp90 inhibitor of the presentinvention is represented by structural formula (LXVI):

R₇₀ and R₇₁, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₇₀ is selected from an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl,haloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₇₁ is as just described. The values for theremainder of the variables are as described for structural formulas(IX), (X), and (XI).

In another preferred embodiment, the Hsp90 inhibitors are represented bystructural formula (LXVIIa) or (LXVIIb):

The variables in formulas (LXVIIa) and (LXVIIb) are defined above withreference to formula (LXVI).

A first preferred set of values for the variables of structural formula(LXVIIa) and (LXVIIb) is provided in the following paragraph:

R₁, R₃ or R₇₁ are each independently selected from —OH, —SH, —NHR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂, and p, R₇₀, R₇, R₈, R₁₀, R₁₁ and R₃₀ are as described forstructural formula (LXVI). Preferably, when R₁, R₃ and R₇₁ have thesevalues, R₁₀ and R₁₁ are preferably each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and p, R₇₀, R₇, and R₃₀ are asdescribed for structural formula (LXVI). More preferably, when R₁, R₃,R₁₀, R₁₁, and R₇₁ have these values, R₇₀ is preferably a C1-C6 alkyl, aC1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl; and p, R₇, R₈ and R₃₀ are as describedfor structural formula (LXVI).

A second preferred set of values for the variables of structural formula(LXVIIa) and (LXVIIb) is provided in the following paragraph:

R₁ and R₃ are each independently —OH, —SH; R₇₀ is preferably a C1-C6alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6alkyl sulfanyl or a C3-C6 cycloalkyl; R₁₀ and R₁₁ are preferably eachindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl; or R₁₀ and R₁₁ taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted nonaromatic, nitrogen-containing heterocyclyl; R₇₁ is —OH,—SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇,—SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇,—SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇,—OP(O)(OR₇)₂ or —SP(O)(OR₇)₂; and p, R₇ R₈ and R₃₀ are as described forstructural formula (LXVI). Preferably, R₃₀ is —OH, —SH, halogen, cyano,a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl and the remainder of the variables are as just described.

A third preferred set of values for the variables of structural formula(LXVIIa) and (LXVIIb) is provided in the following paragraph:

R₁, R₃ and R₇₁ are independently —SH or —OH; R₇₀ is cyclopropyl orisopropyl; R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6straight or branched alkyl, optionally substituted by —OH, —CN, —SH,amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and R₃₀ is —OH, —SH, halogen, cyano, aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl. Preferably, R₃₀ is a methyl, ethyl, propyl, isopropyl,methoxy or ethoxy. More preferably, R₁, R₃, R₇₀, R₇₁ and R₃₀ are as justdescribed and R₁₀ and R₁₁ are each independently a hydrogen, methyl,ethyl, propyl, isopropyl, or taken together with the nitrogen to whichthey are attached, are:

wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another preferred embodiment, the Hsp90 inhibitor is represented bystructural formulas (LXVIIIa) or (LXVIIIb):

The values for the variables in structural formulas (LXVIIIa) and(LXVIIIb) are as described for structural formulas (LXVc) and (LXVd).Preferably, R₃₀ is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇,—OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇,—SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇,—NR₇C(O)OR₇, —NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C, (S)NR₁₀R₁₁,—NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇,—OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇,—SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. More preferably, R₃₀is an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇.

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from formulas (LXIXa)-(LXIXd):

The values of the variables in structural formulas (LXIXa)-(LXIXd) aredefined above with reference to structural formulas (LXVIIIa) and(LXVIIIb).

A first preferred set of values for the variables in structural formulas(LXIXa)-(LXIXd) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH, —SH, —HNR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂;

R₇₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. Preferably, R₇₀ is a C1-C6 alkyl, a C1-C6 haloalkyl, aC1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6cycloalkyl; and

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(LXIXa)-(LXIXd) are as described for structural formulas (LXVIIIa) and(LXVIIIb). Preferably, R₁₀ and R₁₁ are each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl.

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected form formulas (LXXa)-(LXXp):

The values of the variables in structural formulas (LXXa)-(LXXp) aredefined above with reference to structural formulas (LXIXa)-(LXIXd).

A first preferred set of values for the variables in structural formulas(XIVa-p) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH, —SH, —HNR₇;

R₇₀, is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(LXXa)-(LXXp) are as described for structural formulas (LXVIIIa) and(LXVIIIb). Preferably, R₁₀ and R₁₁ are each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and

R₃₀ and the remainder of the variables in structural formulas(LXXa)-(LXXp) are as described for structural formulas (LXIXa)-(LXIXd).Preferably, R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.

A second preferred set of values for the variables in structuralformulas (LXXa)-(LXXp) are as described in the following paragraphs:

R₁ and R₃ are independently —SH or —OH;

R₇₀ is cyclopropyl or isopropyl;

R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R₁₀and R₁₁ taken together with the nitrogen to which they are attached forma substituted or unsubstituted nonaromatic, nitrogen-containingheterocyclyl;

R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R₃₀ is amethyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainderof the variables are as described for formulas (LXVIIIa) and (LXVIIIb).More preferably, R₁₀ and R₁₁ are each independently a hydrogen, methyl,ethyl, propyl, isopropyl, or taken together with the nitrogen to whichthey are attached, are:

-   -   wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another embodiment, the Hsp90 inhibitor of the present invention isrepresented by structural formulas (LXXI) and (LXXII):

In formulas (LXXI) and (LXXII):

X₁₄ is O, S, or NR₇. Preferably, X₁₄ is O;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, or —NHR₇;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl. Preferably, R₂₁ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Alternatively,R₂₁ is

wherein

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl or heteroaryl, an optionally substitutedaralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to which theyare attached, form an optionally substituted heteroaryl or heterocyclyl;and

R₃₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

z and q are independently an integer from 0 to 4; and

x is 0 or 1, provided that z+x less than or equal to 4.

R₂₂, for each occurrence, is independently —H or an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl, a haloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁. Preferably,R₂₂ is —H, an alkyl, an aralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently —H, a substituentselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

i) Exemplary Compounds of the Invention

Exemplary triazole compounds of the invention are depicted in Table 5below, including tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof.

TABLE 5 No. Structure Tautomeric Structure Name 1

3-(2- Hydroxyphenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole 2

3-(2,4- Dihydroxyphenyl)- 4-[4-(2- methoxyethoxy)- naphthalen-1-yl]-5-mercapto-triazole 3

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- bromophenyl)-5-mercapto-triazole 4

3-(2,4- Dihydroxyphenyl)- 4-(4-bromophenyl)- 5-mercapto-triazole 5

3-(3,4- Dihydroxyphenyl)- 4-(6-methoxy- naphthalen-1-yl)-5-mercapto-triazole 6

3-(3,4- Dihydroxyphenyl)- 4-(6-ethoxy- naphthalen-1-yl)-5-mercapto-triazole 7

3-(3,4- Dihydroxyphenyl)- 4-(6-propoxy- naphthalen-1-yl)-5-mercapto-triazole 8

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(5- methoxy- naphthalen-1-yl)-5-mercapto-triazole 9

3-(3,4- Dihydroxyphenyl)- 4-(6-isopropoxy- naphthalen-1-yl)-5-mercapto-triazole 10

3-(2,4- Dihydroxyphenyl)- 4-(2,6- diethylphenyl)-5- mercapto-triazole 11

3-(2,4- Dihydroxyphenyl)- 4-(2-methy-6- ethylphenyl)-5-mercapto-triazole 12

3-(2,4- Dihydroxyphenyl)- 4-(2,6- diisopropylphenyl)-5-mercapto-triazole 13

3-(2,4- Dihydroxyphenyl)- 4-(1-ethyl-indol-4- yl)-5-mercapto- triazole14

3-(2,4- Dihydroxyphenyl)- 4-(2,3-dihydro- benzo[1,4]dioxin-5-yl)-5-mercapto- triazole 15

3-(2,4- Dihydroxyphenyl)- 4-(3-methylphenyl)- 5-mercapto-triazole 16

3-(2,4- Dihydroxyphenyl)- 4-(3-methylphenyl)- 5-mercapto-triazole 17

3-(2,4- Dihydroxyphenyl)- 4-(2-chlorophenyl)- 5-mercapto-triazole 18

3-(2,4- Dihydroxyphenyl)- 4-(3-chlorophenyl)- 5-mercapto-triazole 19

3-(2,4- Dihydroxyphenyl)- 4-(4-chlorophenyl)- 5-mercapto-triazole 20

3-(2,4- Dihydroxyphenyl)- 4-(2- methoxyphenyl)-5- mercapto-triazole 21

3-(2,4- Dihydroxyphenyl)- 4-(3- methoxyphenyl)-5- mercapto-triazole 22

3-(2,4- Dihydroxyphenyl)- 4-(4- methoxyphenyl)-5- mercapto-triazole 23

3-(2,4- Dihydroxyphenyl)- 4-(3-fluorophenyl)- 5-mercapto-triazole 24

3-(2,4- Dihydroxyphenyl)- 4-(2-ethylphenyl)-5- mercapto-triazole 25

3-(2-Hydroxy-4- fluorophenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole26

3-(2-Hydroxy-4- aminophenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole27

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4-butyl- phenyl)-5-mercapto-triazole 28

3-(2,4- Dihydroxyphenyl)- 4-(2,4-dimethyl- phenyl)-5-mercapto- triazole29

3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5-mercapto- triazole30

3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5-mercapto- triazole31

3-(2,4- Dihydroxyphenyl)- 4-(4-fluorophenyl)- 5-mercapto-triazole 32

3-(2,4- Dihydroxyphenyl)- 4-(2- methylsulfanylphenyl)- 5-mercapto-triazole 33

3-(2,4- Dihydroxyphenyl)- 4-(naphthalene-2- yl)-5-mercapto- triazole 34

3-(2,4- Dihydroxyphenyl)- 4-(2,3- dimethylphenyl)-5- mercapto-triazole35

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- fluorophenyl)-5-mercapto-triazole 36

3-(2,4- Dihydroxyphenyl)- 4-(acenaphthalen-5- yl)-5-mercapto- triazole37

3-(2-Hydroxy-4- methoxy-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 38

3-(2,4- Dihydroxyphenyl)- 4-(2,3- dichlorophenyl)-5- mercapto-triazole39

3-(2,4- Dihydroxyphenyl)- 4-(5- methoxynaphthalen- 1-yl)-5-mercapto-triazole 40

3-(2,4- Dihydroxyphenyl)- 4-(pyren-1-yl)-5- mercapto-triazole 41

3-(2,4- Dihydroxyphenyl)- 4-(quinolin-5-yl)-5- mercapto-triazole 42

3-(2,4- Dihydroxyphenyl)- 4-(1,2,3,4- tetrahydronaphthalen-5-yl)-5-mercapto- triazole 43

3-(2,4- Dihydroxyphenyl)- 4-(anthracen-1-yl)- 5-mercapto-triazole 44

3-(2,4- Dihydroxyphenyl)- 4-(biphenyl-2-yl)-5- mercapto-triazole 45

3-(2,4-Dihydroxy-6- methyl-phenyl)-4- (naphthalene-1-yl)-5-mercapto-triazole 46

3-(2,4- Dihydroxyphenyl)- 4-(4- pentyloxyphenyl)-5- mercapto-triazole 47

3-(2,4- Dihydroxyphenyl)- 4-(4- octyloxyphenyl)-5- mercapto-triazole 48

3-(2,4- Dihydroxyphenyl)- 4-(4- chloronaphthalen-1- yl)-5-mercapto-triazole 49

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 50

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(7- carboxymethoxy-naphthalen-1-yl)-5- mercapto-triazole 51

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl- quinolin-4-yl)-5-mercapto-triazole 52

3-(3- Hydroxypyridin-4- yl)-4-(naphthalen-1- yl)-5-mercapto- triazole 53

3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 54

3-(2,4-Dihydroxy- phenyl)-4-(1,2,3,4- tetrahydronaphthalen-1-yl)-5-mercapto- triazole 55

3-(2,4-Dihydroxy- phenyl)-4-(2,3- dihydro- benzo[1,4]dioxin-5-yl)-5-mercapto- triazole 56

3-(2,4-Dihydroxy- phenyl)-4-(3,5- dimethoxyphenyl)- 5-mercapto-triazole57

3-(2,4-Dihydroxy- phenyl)-4-(2,3- dimethyl-1H-indol- 4-yl)-5-mercapto-triazole 58

3-(2,4-Dihydroxy-3- propyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 59

3-(1-ethyl-4- hydroxy-6-oxo-1,6- dihydro-pyridin-3- yl)-4-(naphthalen-1-yl)-5-mercapto- triazole 60

3-(4-hydroxy-6-oxo- pyridin-3-yl)-4- (naphthalen-1-yl)-5-mercapto-triazole 61

3-(2,4-Dihydroxy- phenyl)-4-(3,5-di- tert-butylphenyl)-5-mercapto-triazole 62

3-(2,6-Dihydroxy5- fluoro-pyridin-3-yl) 4-(naphthalen-1-yl)-5-mercapto-triazole 63

3-(2,4-Dihydroxy-5- methyl-phenyl)-4- (naphthalene-1-yl)-5-mercapto-triazole 64

3-[2,4-Dihydroxy- phenyl]-4-(3- benzoylphenyl)-5- mercapto-triazole 65

3-(2,4-Dihydroxy- phenyl)-4-(4- carboxy-naphthalen- 1-yl)-5-mercapto-triazole 66

3-(2,4-Dihydroxy- phenyl)-4-[4-(N,N- dimethylcarbamoyl)-naphthalen-1-yl]-5- mercapto-triazole 67

3-(2,4-Dihydroxy- phenyl)-4-(4- propoxy-naphthalen- 1-yl)-5-mercapto-triazole 68

3-(2,4-Dihydroxy- phenyl)-4-(4- isopropoxy- naphthalen-1-yl)-5-mercapto-triazole 69

3-(2,4-Dihydroxy- phenyl)-4-(5- isopropoxy- naphthalen-1-yl)-5-mercapto-triazole 70

3-(2,4-Dihydroxy- phenyl)-4- (isoquinolin-5-yl)-5- mercapto-triazole 71

3-(2,4-Dihydroxy- phenyl)-4-(5- propoxy-naphthalen- 1-yl)-5-mercapto-triazole 72

3-(2-Hydroxy-4- methanesulfonamino- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 73

3-(2,4-Dihydroxy- 3,6-dimethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 74

3-(2,4-Dihydroxy- phenyl)-4-[7-(2- methoxyethoxy)- naphthalen-1-yl]-5-mercapto-triazole 75

3-(2,4-Dihydroxy-5- hexyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 76

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(4- methoxy- naphthalen-1-yl-5-mercapto-triazole 77

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(6- methoxy-naphthalin-l-yl)-5-mercapto- triazole 78

3-(2,4-Dihydroxy-3- chloro-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 79

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (2,3-dimethy-4- methoxy-phenyl)-5-mercapto-triazole 80

3-(2,4-Dihydroxy- phenyl)-4-(7- isopropoxy- naphthalen-1-yl)-5-mercapto-triazole 81

3-(2,4-Dihydroxy- phenyl)-4-(7-ethoxy- naphthalen-1-yl)-5-mercapto-triazole 82

3-(2,4-Dihydroxy- phenyl)-4-(7- propoxy-naphthalen- 1-yl)-5-mercapto-triazole 83

3-(2-Hydroxy-4- methoxymethyoxy- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 84

3-[2-Hydroxy-4-(2- hydroxy-ethoxy)- phenyl]-4- (naphthalen-1-yl)-5-mercapto-triazole 85

3-(2,4- Dihydroxyphenyl)- 4-(7-methoxy- naphthalen-1-yl)-5-mercapto-triazole 86

3-(2,4- Dihydroxyphenyl)- 4-(5-methoxy- naphthalen-1-yl)-5-mercapto-triazole 87

3-(2,4- Dihydroxyphenyl)- 4-(4-hydroxy- naphthalen-1-yl)-5-mercapto-triazole 88

3-(2,4- Dihydroxyphenyl)- 4-(1-isopropyl- indol-4-yl)-5-mercapto-triazole 89

3-(2,4-Dihydroxy-5- tert-butyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 90

3-(2,4-Dihydroxy-5- propyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 91

3-(2,4-Dihydroxy-3- methyl-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 92

3-(2,4-Dihydroxy-5- isobutyl-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 93

3-(2,4-Dihydroxy- phenyl)-4-(2,3- dimethoxy-phenyl)- 5-mercapto-triazole94

3-(2,4-Dihydroxy- phenyl)-4-(2- methoxy-3-chloro- phenyl)-5-mercapto-triazole 95

3-(2,4-Dihydroxy- phenyl)-4-(indol-4- yl)-5-mercapto- triazole 96

3-(2,4-Dihydroxy- phenyl)-4-[1-(2- methoxyethoxy)- indol-4-yl]-5-mercapto-triazole 97

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- hydroxy-triazole 98

3-(1-Oxo-3- hydroxy-pyridin-4- yl)-4-(naphthalen-1- yl)-5-mercapto-triazole 99

3-(2,5-Dihydroxy-4- carboxy)-4- (naphthalen-1-yl)-5- mercapto-triazole100

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4-yl)-5-mercapto- triazole 101

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-[1- (dimethyl- carbamoyl)-indol-4-yl]-5-mercapto- triazole 102

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-benzoimidazol-4-yl)-5-mercapto- triazole 103

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (1,2,3-trimethyl- indol-5-yl)-5-mercapto-triazole 104

3-(2,5-Dihydroxy-4- hydroxymethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 105

3-(2-Hydroxy-4- amino-phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole106

3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 107

3-(2,4-Dihydroxy-3- chloro-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 108

3-(2,4-Dihydroxy-3- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole109

3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-phenyl)-5- mercapto-triazole 110

3-(2,4-Dihydroxy- phenyl)-4-(2,5- dimethoxy-phenyl)- 5-mercapto-triazole111

3-(2,4-Dihydroxy- phenyl)-4-phenyl-5- mercapto-triazole 112

3-(2-Hydroxy- phenyl)-4-(2- methoxy-phenyl)-5- mercapto-triazole 113

3-(2-Hydroxy- phenyl)-4-(4- methyl-phenyl)-5- mercapto-triazole 114

3-(2-Hydroxy- phenyl)-4-(4-bromo- phenyl)-5-mercapto- triazole 115

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (methyl sulfanyl)-triazole 116

3-(2,4-Dimethoxy- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole 117

3-[2,4-Di-(dimethyl- carbamoyloxy)- phenyl]-4- (naphthalen-1-yl)-5-(dimethyl- carbomoylsulfanyl)- triazole 118

3-(2.4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (dimethylcarbamoylsulfanyl)-triazole 119

3-(2,4- Diethoxycarbonyloxy- phenyl)-4- (naphthalen-1-yl)-5-(ethoxycarbonyl- sulfanyl)-triazole 120

3-(2,4-Di- isobutyryloxy- phenyl)-4- (naphthalen-1-yl)-5-(isobutyrylsulfanyl)- triazole 121

3-[2,4-Di-(dimethyl- carbamoyloxy)- phenyl]-4-(quinolin-5-yl)-5-(dimethyl- carbamoylsulfanyl)- triazole 122

3-(2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)-5- (acetylsulfanyl)-triazole 123

3-(2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole 124

3-(2,4- Diethoxycarbonyloxy- phenyl)-4- (naphthalen-1-yl)-5-(ethylcarbamoyl- sulfanyl)-triazole 125

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (2-hydroxyethylsul-fanyl)-triazole 126

3-(2,4-Dihydroxy- phenyl)-4-ethyl-5- mercapto-triazole 127

3-(2,4-Dihydroxy- phenyl)-4-propyl-5- mercapto-triazole 128

3-(2,4-Dihydroxy- phenyl)-4-isopropyl- 5-mercapto-triazole 129

3-(2,4-Dihydroxy- phenyl)-4-ethyl-5- mercapto-triazole 130

3-(2,4-Dihydroxy- phenyl)-4- cyclopropyl-5- mercapto-triazole 131

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)-5- (carboxyethysulfanyl)-triazole 132

3-(2,6-Dimethoxy-5- fluoro-pyridin-3-yl)- 4-(naphthalen-1-yl)-5-mercapto-triazole 133

3-(2- Methanesulfonyloxy- 4- methanesulfonyl- amino-phenyl)-4-(naphthalen-1-yl)-5- mercapto-triazole 134

3-(2-Methoxy- phenyl)-4-(4- methoxy-phenyl)-5- mercapto-triazole 135

3-(3-Hydroxy- naphthalen-2-yl)-4- phenyl-5-mercapto- triazole 136

3-(2-Methoxy- phenyl)-4-(4- methyl-phenyl)-5- mercapto-triazole 137

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- methox-phenyl)-5-hydroxy-triazole 138

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5-hydroxy-triazole 139

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-3-yl)-5-hydroxy- triazole 140

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4-yl)-5-amino-triazole 141

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- methoxy-phenyl)-5-amino-triazole 142

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (naphthalen-1-yl)-5- amino-triazole143

3-(2-Hydroxy-5- ethyloxy-phenyl)-4- (naphthalen-1-yl)-5-hydroxy-triazole 144

3-(2-Hydroxy-5- isopropyl-phenyl)-4- (naphthalen-1-yl)-5-hydroxy-triazole 145

3-(2-Dihydroxy- phenyl)-4-(7-fluoro- naphthalen-1-yl)-5-hydroxy-triazole 146

3-(2,4-Dihydroxy- phenyl)-4-(2,3- difluorophenyl)-5- hydroxy-triazole147

3-(2,4-Dihydroxy- phenyl)-4-[2-(1H- tetrazol-5-yl)- phenyl]-5-hydroxy-triazole 148

3-(2,4-Dihydroxy- phenyl)-4- (benzothiazol-4-yl)- 5-hydroxy-triazole 149

3-(2,4-Dihydroxy- phenyl)-4-(9H- purin-6-yl)-5- hydroxy-triazole 150

3-(2,4-Dihydroxy- phenyl)-4-{4-[2- (moropholin-1-yl)- ethoxy]-phenyl}-5-hydroxy-triazole 151

3-(2,4-Dihydroxy- phenyl)-4- cyclopentyl-5- hydroxy-triazole 152

3-(2,4-Dihydroxy- phenyl)-4-phenyl-5- (sulfamoylamino)- triazole 153

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)-5-ureido-triazole 154

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (2,3- difluorophenyl)-5-ureido-triazole 155

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-indol-4-yl)-5-ureido-triazole 156

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (quinolin-5-yl)-5- ureido-triazole157

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)-5-carbamoyloxy- triazole 158

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3- trifluoromethyl- phenyl)-5-carbamoyloxy- triazole 159

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- methyl-indol-4-yl)-5-carbamoyloxy- triazole 160

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (8-methoxy- quinolin-5-yl)-5-carbamoyloxy- triazole 161

3-(2,4-Dihydroxy-5- isopropyl-phenyl)-4- (3-methyl-quinolin- 5-yl)-5-carboxyamino- triazole 162

3-(2,4-Dihydroxy- phenyl)-4-(1- methyl-2-chloro- indol-4-yl)-5-carbamoyloxy- triazole 163

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- [3,5-di- (trifluoromethyl)-phenyl]-5- carbamoyloxy- triazole 164

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-trifluoromethyl- phenyl)-5-(sulfamoylamino)- triazole 165

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)-5-(sulfamoylamino)- triazole 166

3-(2,4-Dihydroxy-5- methoxy-phenyl-4- (1-isopropyl- benzoimidazol-4-yl)-5- (sulfamoylamino)- triazole 167

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-isopropylphenyl)- 5-(thiocarboxyamino)- triazole 168

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (3-isopropyloxy- phenyl)-5-(sulfamoyloxy)- triazole 169

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalene-1-yl)-5-(sulfamoyloxy)- triazole 170

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (1-isopropyl- benzoimidazol-4-yl)-5- (sulfamoyloxy)- triazole 171

3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-methoxy-phenyl)- 4-(1-isopropyl-benzoimidazol-4- yl)-5-hydroxy- triazole 172

3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-ethyl-phenyl)-4-(naphthalin-2-yl)-5- hydroxy-triazole 173

3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- ethyl-phenyl]-4-(naphthalin-2-yl)-5- hydroxy-triazole 174

3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- chloro-phenyl]-4-(quinolin-5-yl)-5- mercapto-triazole 175

3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- ethyl-pheny]-4-(2,3-difluoro- phenyl)-5-mercapto- triazole 176

3-[2-Hydroxy-4- isobutyryloxy-5- ethyl-phenyl]-4-(1- methyl-benzo-imidazol-4-yl)-5- hydroxy-triazole 177

3-(2,4-Dihydroxy-5- methoxy-phenyl)-4- (naphthalen-1-yl)-5-mercapto-triazole 178

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(5- hydroxy-naphthalen-l-yl)-5-mercapto- triazole 179

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1- ylmethyl)-5-mercapto-triazole 180

3-(2-Hydroxy-4- methoxyphenyl)-4- (naphthalen-1-yl)-5- mercapto-triazole181

3-(2,4-Dihydroxy- phenyl)-4-(biphenyl- 3-yl)-5-mercapto- triazole 182

3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-5- hydroxymethyl-phenyl)-5-mercapto- triazole 183

3-(2,4-Dihydroxy- phenyl)-4-(1- dimethylcarbamoyl- indol-4-yl)-5-mercapto-triazole 184

3-(2,4,5-Trihydroxy- phenyl)-4- (naphthalene-1-yl)- 5-mercapto-triazole185

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4- (2,3-dimethyl-indol-5-yl)-5-mercapto- triazole 186

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(3-t- butyl-4-methoxy-phenyl)-5-mercapto- triazole 187

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-1H- benzoimidazol-4-yl)-5-mercapto- triazole, HCl salt 188

3-(2,4-Dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7- methoxy-indol-4-yl)-5-mercapto- triazole 189

3-(2,4-Dihydroxy-5- cyclopropyl- phenyl)-4- (naphthalene-1-yl)-5-mercapto-triazole 190

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- propyl-indol-4-yl)-5-mercapto-[1,2,4] triazole 191

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- acetyl-2,3-dimethyl-indol-5-yl)-5- mercapto-[1,2,4] triazole 192

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-3-ethyl-benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole 193

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- ethyl-2-methyl-benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole 194

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- propyl-2,3-dimethyl-indol-5-yl)-5- mercapto-[1,2,4] triazole 195

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl- tetrahydrocarbozol-7-yl)-5-mercapto- [1,2,4] triazole 196

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl- cyclononan[a]indol-5-yl)-5-mercapto- [1,2,4] triazole 197

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-butyl-indol-4-yl)-5-mercapto-[1,2,4] triazole 198

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-pentyl-indol-4-yl)-5-mercapto-[1,2,4] triazole 199

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- n-hexyl-indol-4-yl)-5-mercapto-[1,2,4] triazole 200

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1-(1- methylcyclopropyl)-indol-4-yl)-5- mercapto-[1,2,4] triazole 201

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1- isopropyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 202

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1,2,3- trimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 203

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7- methoxy-indol-4-yl)-5-mercapto- [1,2,4] triazole disodium salt 204

3-(2,4-dihydroxy-5- tert-butyl-phenyl)-4- (1-isopropyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 205

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1-propyl- 7-methoxy-indol-4-yl)-5-mercapto- [1,2,4] triazole 206

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- methyl-3-ethyl- indol-5-yl)-5-mercapto-[1,2,4] triazole 207

3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,3-dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 208

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-isopropyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 209

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- methyl-3-isopropyl-indol-5-yl)-5- mercapto-[1,2,4] triazole 210

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- ethyl-carbozol-7-yl)-5-mercapto-[1,2,4] triazole 211

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7-hydroxy-indol-4-yl)- 5-mercapto-[1,2,4] triazole 212

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(1- isopropyl-7-ethoxy-indol-4-yl)-5- mercapto-[1,2,4] triazole 213

3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,2-dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 214

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(N- methyl-indol-5-yl)-5-mercapto-[1,2,4] triazole 215

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-7-methoxy-benzofuran-4-yl)-5- mercapto-[1,2,4] triazole 216

3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (benzofuran-5-yl)-5-mercapto-[1,2,4] triazole 217

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- methyl-1,3- benzoxaz-5-yl)-5-mercapto-[1,2,4] triazole 218

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 219

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1,3- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 220

3-(2,4-dihydroxy-5- ethyl-phenyl)-4- (1,3-dimethyl-indol-5-yl)-5-hydroxy- [1,2,4] triazole 221

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (N-methyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 222

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,2-dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 223

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-dimethyl-indol-5-yl)-5-hydroxy- [1,2,4] triazole 224

3-(2,4-dihydroxy-5- cyclopropyl- phenyl)-4-(1- methyl-indol-5-yl)-5-mercapto-[1,2,4] triazole 225

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1H-indol-5-yl)-5-mercapto-[1,2,4] triazole 226

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indol-5-yl)-5-hydroxy- [1,2,4] triazole 227

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-ethyl-indol-5-yl)-5-mercapto-[1,2,4] triazole 228

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-propyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 229

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-2- trifluoromethyl-benzimidazol-5-yl)- 5-mercapto-[1,2,4] triazole 230

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indazol-5-yl)-5-mercapto- [1,2,4] triazole 231

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-methyl-indazol-6-yl)-5-mercapto- [1,2,4] triazole 232

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1-isopropyl-indol-4-yl)-5-hydroxy- [1,2,4] triazole 233

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (1,3-benzodiaxol-5-yl)-5-mercapto- [1,2,4] triazole 234

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (indan-5-yl)-5-mercapto-[1,2,4] triazole 235

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (2-methyl-indazol-6-yl)-5-mercapto- [1,2,4] triazole 236

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(3- oxo- benzo[1,4]oxazin-6-yl)-5-mercapto- [1,2,4] triazole 237

3-(2,4-dihydroxy-5- ethyl-phenyl)-4-(2- oxo-1,3-dihydro-benzoimidazol-5- yl)-5-mercapto- [1,2,4] triazole 238

3-(2,4-dihydroxy-5- isopropyl-phenyl)-4- (2H- benzo[1,4]oxazin-6-yl)-5-mercapto- [1,2,4] triazole 239

4-Ethyl-6-[5- mercapto-4-(1- methyl-2,3-dihydro- 1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]- benzene-1,3-diol 240

5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-4-yl)indolin- 2-one 241

5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-4-yl)-1H- benzo[d]imidazol- 2(3H)-one 242

5-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-4-yl)-1- methylindolin-2-one 243

4-isopropyl-6-(5- mercapto-4-(4- propyl-3,4-dihydro- 2H-benzo[b][1,4]oxazin- 6-yl)-4H-1,2,4- triazol-3-yl)benzene- 1,3-diol 244

6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-4-yl)-2H- benzo[b][1,4]oxazin- 3(4H)-one 245

6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-4-yl)-3- methylbenzo[d]thiazol- 2(3H)-one 246

6-(3-(5-ethyl-2,4- dihydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-4-yl)benzo[d]thiazol- 2(3H)-one 247

4-(4-(3- (diethylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 248

4-(4-(3-(N- isopropyl-N- propylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol 249

4-(4-(3-(N- isopropyl-N- methylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol 250

4-(4-(3-(N-ethyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 251

4-(4-(3- (dimethylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 252

4-(4-(3- (dimethylamino) phenyl)- 5-mercapto-4H- 1,2,4-triazol-3-yl)-6-ethylbenzene-1,3- diol 253

4-(4-(3-(N-ethyl-N- isopropylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- ethylbenzene-1,3- diol 254

4-ethyl-6-(5- mercapto-4-(3- (pyrrolidin-1- yl)phenyl)-4H-1,2,4-triazol-3-yl)benzene- 1,3-diol 255

4-ethyl-6-(5- mercapto-4-(4- methoxy-3- morpholinophenyl)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 256

4-(4-(3-(N- isopropyl-N- propylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 257

4-(4-(3-(N-methyl- N-propylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 258

4-(4-(3-(N-methyl- N-ethylamino)-4- methoxy-phenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 259

4-(4-(4- (dimethylamino)-3- methoxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 260

261

4-(4-(3- aminophenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6-ethylbenzene-1,3- diol 262

263

4-(4-(3-(N- isopentyl-N- methylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 264

265

4-(4-(3-(N-(2- (dimethylamino)ethyl)- N-methylamino)- 4-methoxyphenyl)-5-mercapto-4H- 1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol 266

4-(4-(3-(N-(2- methoxyethyl)-N- methylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 267

4-(4-(3-(N- (cyclopropylmethyl)- N-methylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 268

4-(4-(3-(N-butyl-N- methylamino)-4- methoxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol 269

4-(4-(3-(N-isobutyl- N-methylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 270

4-(4-(3-(N-(2-1H- imidazol-1-yl)ethyl)- N-methylamino)-4-methoxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene-1,3-diol 271

4-(4-(3-(N-methyl- N-propylamino)-4- methoxyphenyl)-5-mercapto-4H-1,2,4- triazol-3-yl)-6- isopropylbenzene- 1,3-diol 272

4-(4-(3- (dimethylamino)-4- (methylthio)phenyl)- 5-mercapto-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol 273

4-(4-(3-(1H-pyrrol- 1-yl)phenyl)-5- hydroxy-4H-1,2,4- triazol-3-yl)-6-ethylbenzene-1,3- diol 274

4-(4-(3-(1H- imidazol-1- yl)phenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene- 1,3-diol 275

276

277

4-(4-(4- (dimethylamino) phenyl)-5-mercapto- 4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3- diol 278

4-(4-(4-(diethylamino) phenyl)-5-mercapto- 4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3- diol 279

4-ethyl-6-(5- mercapto-4-(4- morpholinophenyl)- 4H-1,2,4-triazol-3-yl)benzene-1,3-diol 280

4-(4-(4-(1H- imidazol-1- yl)phenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 281

4-(4-(2,5-diethoxy- 4- morpholinophenyl)- 5-mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 282

4-(4-(3-(1H-pyrrol- l-yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6-ethylbenzene-1,3- diol 283

4-(4-(4-(1H-pyrazol- 1-yl)phenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6-ethylbenzene-1,3- diol 284

4-(4-(4-(amino)-3- hydroxyphenyl)-5- mercapto-4H-1,2,4- triazol-3-yl)-6-ethylbenzene-1,3- diol 285

4-(4-(4- (methylamino)-3- hydroxyphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol 286

4-(4-(4- (dimethylamino)-3- methylphenyl)-5- mercapto-4H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3- diol

Exemplary pyrazole compounds of the invention are depicted in Table 6below, including tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof.

TABLE 6 No. Structure Name 287

4-[3-(N,N-diethylamino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 288

4-[3-(isopropyl-propyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 289

4-[3-(isopropyl-methyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 290

4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 291

4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 292

4-[3-(N,N-methylamino)-phenyl]-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 293

4-[4-(N,N-methylamino)-3-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 294

4-[3-(isopropyl-ethyl-amino)-4- methoxy-phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 295

4-[3-(pyrrolidin-1-yl)-phenyl]-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 296

4-[3-(isopropyl-propyl-amino)-4- methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 297

4-[3-(methyl-propyl-amino)-4-methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 298

4-[3-(ethyl-methyl-amino)-4-methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 299

4-[3-(morpholino-1-yl)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 300

4-[3-(ethyl-methyl-amino)-4-methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy- phenyl)-5-hydroxy-2H-pyrazole 301

4-[3-(N,N-diethyl-amino)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 302

4-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 303

4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-cyclopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H- pyrazole 304

4-[3-(ethyl-methyl-amino)-4-methoxy- phenyl]-3-(5-cyclopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 305

Phosphoric acid mono {4-[3-(ethyl- methyl-amino)-4-methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy-phenyl)-2H- pyrazol-5-yl} ester 306

Phosphoric acid {4-[3-(ethyl-methyl- amino)-4-methoxy-phenyl]-3-(5-isopropyl-2,4-dihydroxy-phenyl)-2H- pyrazol-5-yl} ester ethyl ester 307

4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-isopropyl-2-hydroxy-4-dimethylaminocarbamoyloxy-phenyl)- 5-mercapto-2H-pyrazole 308

4-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-3-(5-isopropyl-2-hydroxy-4-dimethylaminocarbamoyloxy-phenyl)- 5-mercapto-2H-pyrazole 309

4-[3-(N,N-methylamino)-4-methoxy- phenyl]-3-(5-isopropyl-2,4-dihydroxy-phenyl)-5-(2-hydroxy-ethylsulfanyl)- 2H-pyrazole 310

4-(1-isopropyl-1H-indol-4-yl)-3-(2,4- dihydroxy-phenyl)-5-mercapto-2H-pyrazole 311

4-(1H-indol-4-yl)-3-(2,4-dihydroxy- phenyl)-5-mercapto-2H-pyrazole 312

4-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-3-(2,4-dihydroxy-phenyl)-5-mercapto- 2H-pyrazole 313

4-(1-isopropyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 314

4-(1-dimethylcarbamoyl-1H-indol-4-yl)-3-(2,4-dihydroxy-phenyl)-5-mercapto- 2H-pyrazole 315

4-(1-propyl-1H-indol-4-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 316

4-(1-ethyl-1H-indol-4-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 317

4-(1,2,3-trimethyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 318

4-(2,3-dimethyl-1H-indol-4-yl)-3-(5- ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 319

4-(1-ethyl-1H-benzoimidazol-4-yl)-3- (5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 320

4-(1-carboxy-2,3-dimethyl-1H-indol-5-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5- mercapto-2H-pyrazole 321

4-(1-ethyl-2-methyl-1H-benzoimidazol-6-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole 322

4-(1-isopropy-7-methoxy-1H-indol-4-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole 323

4-(1-propy-2,3-dimethyl-1H-indol-5-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)- 5-mercapto-2H-pyrazole 324

4-(1-ethyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 325

4-(1-ethyl-1H-indol-4-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 326

4-(1,2,3-trimethyl-1H-indol-5-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-amino- 2H-pyrazole 327

4-(1-isopropyl-7-methoxy-1H-indol-4-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5- amino-2H-pyrazole 328

4-(1-isopropyl-7-methoxy-1H-indol-4- yl)-3-(5-isopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 329

4-(1,3-dimethyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 330

4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 331

4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 332

4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-amino-2H-pyrazole 333

4-(7-methoxy-benzofuran-4-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 334

4-(5-methoxy-naphthalene-1-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 335

4-(benzo[l,4]dioxin-5-yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 336

4-(acenaphthen-5-yl)-3-(5-isopropyl- 2,4-dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 337

4-(9H-purin-6-yl)-3-(5-isopropyl-2,4- dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 338

4-(benzothiazol-4-yl)-3-(5-isopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 339

4-(7-fluoro-naphthylen-1-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5-mercapto-2H-pyrazole 340

4-(quinolin-4-yl)-3-(5-isopropyl-2,4- dihydroxy-phenyl)-5-mercapto-2H-pyrazole 341

4-(1-methyl-1H-indol-5-yl)-3-(5- isopropyl-2,4-dihydroxy-phenyl)-5-carbamoyloxy-2H-pyrazole 342

4-(1-methyl-1H-indol-5-yl)-3-(5- cyclopropyl-2,4-dihydroxy-phenyl)-5-carboxyamino-2H-pyrazole 343

4-(1-methyl-1H-indol-5-yl)-3-(5- methoxy-2,4-dihydroxy-phenyl)-5-aminosulfamido-2H-pyrazole 344

4-(4-methoxy-naphthalene-1-yl)-3-(5- isopropyl-2-hydroxy-4-ethoxycarbonyloxy-phenyl)-5- mercapto-2H-pyrazole 345

4-(naphthalene-1-yl)-3-(5-isopropyl-2,4-ethylcarbamoyloxy-phenyl)-5-mercapto- 2H-pyrazole 346

4-(1-methyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-ethylcarbamoyloxy-phenyl)-5-dimethylcarbamoylsulfanyl- 2H-pyrazole 347

4-(1,2-dimethyl-1H-indol-4-yl)-3-(5- isopropyl-2,4-ethyloxycarbonyloxy-phenyl)-5-ethoxycarbamoylsulfanyl- 2H- pyrazole 348

4-(naphthalen-1-yl)-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-hydroxy-2H-pyrazole 349

4-(2-methyl-4-fluorophenyl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-2H- pyrazole 350

4-(3,5-dimethoxyphenyl)-3-(5-ethyl-2,4- dihydroxy-phenyl)-5-amino-2H-pyrazole 351

4-[2-(1H-tetrazol-5-yl)-phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl)-5-hydroxy- 2H-pyrazole

Exemplary imidazolyl compounds of the invention are depicted in Table 7below, including tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof.

TABLE 7 No. Structure Name 352

1-(3-diethylamino-4-methoxy-phenyl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 353

1-[3-(propyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 354

1-[3-(methyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 355

1-[3-(methyl-ethylamino)-4-methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 356

l-(3-dimethylamino-4-methoxy- phenyl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 357

1-(3-dimethylamino-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 358

1-(3-methoxy-4-dimethylamino- phenyl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 360

1-[3-(ethyl-isopropylamino)-4-methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 361

1-(3-pyrrolidin-1-yl-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 362

1-[3-(propyl-isopropylamino)-4- methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 363

1-[3-(methyl-propylamino)-4-methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole364

1-[3-(methyl-ethylamino)-4-methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole365

1-[3-(morpholino-1-yl)-4-methoxy- phenyl]-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 366

1-[3-(methyl-ethylamino)-4-methoxy-phenyl]-2-hydroxy-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 367

1-(3-diethylamino-4-methoxy-phenyl)- 2-hydroxy-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 368

1-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-2-hydroxy-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 369

1-[3-(methyl-ethylamino)-4-methoxy-phenyl]-2-hydroxy-5-(2,4-dihydroxy-5- cyclopropyl-phenyl)-1H-imidazole370

1-[3-(methyl-ethylamino)-4-methoxy-phenyl]-2-mercapto-5-(2,4-dihydroxy-5- cyclopropyl-phenyl)-1H-imidazole371

1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-phosphonooxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 372

1-[3-(methyl-ethylamino)-4-methoxy- phenyl]-2-(ethoxy-hydroxy-phosphoryloxy)-5-(2,4-dihydroxy-5- isopropyl-phenyl)-1H-imidazole 373

1-(3-dimethylamino-4-methoxy- phenyl)-2-mercapto-5-(2-hydroxy-4-dimethylcarbamoyloxy-5-isopropyl- phenyl)-1H-imidazole 374

1-[3-(pyrrolidin-1-yl)-4-methoxy- phenyl]-2-mercapto-5-(2-hydroxy-4-isobutyryloxy-5-isopropyl-phenyl)-1H- imidazole 375

1-(3-dimethylamino-4-methoxy- phenyl)-2-(2-hydroxy-ethylsulfanyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 376

1-(1-ethyl-1H-indol-4-yl)-2-mercapto-5-(2,4-dihydroxy-phenyl)-1H-imidazole 377

1-(1-isopropyl-1H-indol-4-yl)-2- mercapto-5-(2,4-dihydroxy-phenyl)-1H-imidazole 378

1-(1H-indol-4-yl)-2-mercapto-5-(2,4- dihydroxy-phenyl)-1H-imidazole 379

1-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-2-mercapto-5-(2,4-dihydroxy-phenyl)- 1H-imidazole 380

1-(1-isopropyl-1H-indol-4-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 381

1-(1-dimethylcarbamoyl-1H-indol-4-yl)-2-mercapto-5-(2,4-dihydroxy-phenyl)- 1H-imidazole 382

1-(1-propyl-1H-indol-4-yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 383

1-(1-ethyl-1H-indol-4-yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 384

1-(1,2,3-trimethyl-1H-indol-5-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 385

1-(2,3-dimethyl-1H-indol-5-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 386

1-(1-ethyl-1H-benzoimidazol-4-yl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 387

1-(1-carboxy-2,3-dimethyl-1H-indol-5- yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 388

1-(1-ethyl-2-methyl-1H-benzoimidazol-6-yl)-2-mercapto-5-(2,4-dihydroxy-5- ethyl-phenyl)-1H-imidazole 389

1-(1-isopropyl-7-methoxy-1H-indol-4- yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 390

1-(1-propyl-2,3-dimethyl-1H-indol-5- yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 391

1-(1-ethyl-1H-indol-4-yl)-2-hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 392

1-(1-ethyl-1H-indol-4-yl)-2-hydroxy-5-(2,4-dihydroxy-5-cyclopropyl-phenyl)- 1H-imidazole 393

1-(1,2,3-trimethyl-1H-indol-5-yl)-2- amino-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 394

1-(1-isopropyl-7-methoxy-1H-indol-4-yl)-2-amino-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 395

1-(1-isopropyl-7-methoxy-1H-indol-4- yl)-2-hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H-imidazole 396

1-(1,3-dimethyl-1H-indol-5-yl)-2- hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H-imidazole 397

1-(1-methyl-1H-indol-5-yl)-2-hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)- 1H-imidazole 398

1-(1-methyl-1H-indol-5 -yl)-2-mercapto-5-(2,4-dihydroxy-5-isopropyl-phenyl)- 1H-imidazole 399

1-(9-methyl-6,7,8,9-tetrahydro-5H- carbazol-3-yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H- imidazole 400

1-(1-methyl-1H-indol-5-yl)-2-amino-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 401

1-(7-methoxy-benzofuran-4-yl)-2- hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H-imidazole 402

1-(5-methoxy-naphthylen-1-yl)-2- mercapto-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H-imidazole 403

1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-mercapto-5-(2,4-dihydroxy-5-ethyl- phenyl)-1H-imidazole 404

1-(3-acenaphthylen-5-yl)-2-hydroxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 405

1-(9H-purin-6-yl)-2-hydroxy-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H-imidazole 406

1-(benzothiazol-4-yl)-2-mercapto-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H- imidazole 407

1-(7-fluoro-naphthylen-1-yl)-2- mercapto-5-(2,4-dihydroxy-5-cyclopropyl-phenyl)-1H-imidazole 408

1-(quinolin-4-yl)-2-mercapto-5-(2,4- dihydroxy-5-isopropyl-phenyl)-1H-imidazole 409

1-(1-methyl-indol-5-yl)-2- carbamoyloxy-5-(2,4-dihydroxy-5-isopropyl-phenyl)-1H-imidazole 410

1-(1-methyl-indol-5-yl)-2- carboxyamino-5-(2,4-dihydroxy-5-cycolpropyl-phenyl)-1H-imidazole 411

1-(1-methyl-1H-indol-5-yl)-2- aminosulfamido-5-(5-methoxy-2,4-dihydroxy-phenyl)-1H-imidazole 412

1-(4-methoxy-naphthylen-1-yl)-2- mercapto-5-(2-hydroxy-4-ethoxycarbonyloxy-5-isopropyl- phenyl)-1H-imidazole 413

1-(naphthylen-1-yl)-2-mercapto-5-[2,4-di-(ethoxycarbamoyloxy)-5-isopropyl- phenyl]-1H-imidazole 414

1-(1-methyl-1H-indol-4-yl)-2- dimethylcarbamoylsulfanyl-5-[2,4-di-(ethoxycarbamoyloxy)-5-isopropyl- phenyl]-1H-imidazole 415

1-(1,2-dimethyl-1H-indol-4-yl)-2- ethoxycarbonylsulfanyl-5-[2,4-di-(ethoxycarbonyloxy)-5-isopropyl- phenyl]-1H-imidazole 416

1-(naphthylen-1-yl)-2-hydroxy-5-(2,4- dihydroxy-5-ethyl-phenyl)-1H-imidazole 417

1-(2,5-dimethoxyphenyl)-2-amino-5- (2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 418

1-(2-methyl-4-fluoro-phenyl)-2- mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole 419

1-[2-(1H-tetrazol-5-yl)-phenyl]-2- hydroxy-5-(2,4-dihydroxy-5-ethyl-phenyl)-1H-imidazole

Preferred triazole compounds of the invention are those compounds thatcan form a tautomeric structure as shown below and as exemplified by thetautomeric structures shown in Table 5:

Also preferred are compounds which can be metabolized or hydrolyzed invivo to a compound which can form the tautomeric structure shown above.For example, the following embodiments of a compound of formula (I) canbe produced in vivo in the following reaction:

Without wishing to be bound by any theory, it is believed that thecompounds of the invention preferentially bind to Hsp90 in thetautomeric form shown above, and thereby inhibit the activity of Hsp90.

It is understood that the pyrazole compounds of the present invention,including compounds of formulas (VI) through (VIII) and Table 6 can bepurified, isolated, obtained and used in a form of a pharmaceuticallyacceptable salt, a solvate, a clathrate, a tautomer or a prodrug.

For example, a compound of formula (VI) can undergo the followingtautomerization:

where X⁰ is O, S, or NR₇. It is understood that where a structuralformula is depicted, all possible tautomeric forms of the compound areencompassed within that formula.

Similarly, prodrugs, i.e. compounds which can be metabolized orhydrolyzed in vivo to a compound of the present invention areencompassed by the present description. For example, the followingembodiments of a compound of formula (VI) can be produced in vivo in thefollowing reaction:

One skilled in the art will understand that other hydrolyzableprotecting groups can be employed with the compounds of the presentinvention to obtain prodrugs encompassed by the present description.

It is understood that the compounds of the present invention, includingcompounds of formulas (IX) through (XI) and Tables 7 can be purified,isolated, obtained and used in a form of a pharmaceutically acceptablesalt, a solvate, a clathrate, a tautomer or a prodrug.

For example, a compound of formula (IX) can undergo the followingtautomerization:

where X⁰ is O, S, or NR₇. It is understood that where a structuralformula is depicted, all possible tautomeric forms of the compound areencompassed within that formula.

Similarly, prodrugs, i.e. compounds which can be metabolized orhydrolyzed in vivo to a compound of the present invention areencompassed by the present description. For example, the followingembodiments of a compound of formula (IX) can be produced in vivo in thefollowing reaction:

One skilled in the art will understand that other hydrolyzableprotecting groups can be employed with the compounds of the presentinvention to obtain prodrugs encompassed by the present description.

C. Methods for Making Compounds of the Invention

Methods of making the compounds of the invention are disclosed in U.S.patent application Ser. No. 11/282,119, filed on Nov. 17, 2005; and inU.S. Provisional Patent Application Ser. No. 60/709,310, filed Aug. 18,2005; U.S. Provisional Patent Application Ser. No. 60/724,105, filedOct. 6, 2005; U.S. Provisional Patent Application Ser. No. 60/709,358,filed Aug. 18, 2005; U.S. Provisional Patent Application Ser. No.60/725,044, filed Oct. 6, 2005; U.S. Provisional Patent Application Ser.No. 60/707,836, filed Aug. 12, 2005; U.S. Provisional Patent ApplicationSer. No. 60/709,228, file Aug. 18, 2005; the entire teachings of each ofthese patent applications is incorporated herein by reference.

Additional methods of preparing the compounds of the invention can befound in the following U.S. provisional applications: U.S. Provisionalpatent Application Ser. No. 60/808,376, filed on May 25, 2006; U.S.Provisional patent Application Ser. No. 60/808,342, filed on May 25,2006; U.S. Provisional patent Application Ser. No. 60/808,375, filed onMay 25, 2006; U.S. Provisional patent Application Ser. No. 60/902,031,filed on Feb. 16, 2007; and Attorney Docket No. 3211.1042-002, entitled“Synthesis of Triazole Compounds that Modulate HSP90 Activity,” filed onMay 25, 2007, the entire teachings of each of these applications areincorporated herein by reference.

D. Uses of Compounds of the Invention

The present invention is directed to therapies which involveadministering one or more compounds of the invention, or compositionscomprising said compounds to a subject, preferably a human subject, toinhibit the activity of Hsp90 or to prevent, treat, manage, orameliorate a proliferative disorder, such as cancer (including c-Metassociated cancers), or one or more symptoms thereof.

In another embodiment, the present invention is directed to a method ofinducing degradation of c-Met protein in a subject, comprisingadministering to the subject an effective amount of a compoundrepresented by formula (I) through (LXXII), or any embodiment thereof,or a compound shown in Table 5, 6, or 7. In one embodiment, the subjectis a mammal, preferably a human. In another embodiment, the compound isadministered with one or more additional therapeutic agents. In apreferred embodiment, the additional therapeutic agent is an anticanceragent.

In one embodiment, the present invention is directed to a method oftreating cancer in which dysregulation of c-Met has been implicated as acontributing factor in a subject. The method comprises administering tothe subject in need of treatment for such a cancer an effective amountof a compound represented by formula (I) through (LXXII), or anyembodiment thereof, or a compound shown in Table 5, 6, or 7. In oneembodiment, the subject is a mammal, preferably a human. In anotherembodiment, the compound is administered with one or more additionaltherapeutic agents. In a preferred embodiment, the additionaltherapeutic agent is an anticancer agent.

In another aspect, the invention provides a method for treating a c-Metassociated cancer in a mammal, comprising administering to the mammal aneffective amount of a compound represented by formula (I) through(LXXII), or any embodiment thereof, or a compound shown in Table 5, 6,or 7. In one embodiment, the subject is a mammal, preferably a human. Inanother embodiment, the compound is administered with one or moreadditional therapeutic agents. In a preferred embodiment, the additionaltherapeutic agent is an anticancer agent.

In one embodiment, the invention provides a method for treating a c-Metassociated cancer in a mammal, wherein the c-Met associated cancer hasdeveloped a resistance to treatment with a tyrosine kinase inhibitor.This method comprises administering to the mammal an effective amount ofa compound represented by formula (I) through (LXXII), or any embodimentthereof, or a compound shown in Table 5, 6, or 7. In one embodiment, thetyrosine kinase inhibitor that the c-Met associate cancer has developeda resistance to inhibits the kinase activity of c-Met. In oneembodiment, the tyrosine kinase inhibitor that the c-Met associatecancer has developed a resistance to does not substantially inhibit thekinase activity of c-Met. In another embodiment, the compound isadministered with one or more additional therapeutic agents. In apreferred embodiment, the additional therapeutic agent is an anticanceragent.

In another embodiment, the invention provides a method of treatingcancer in a subject, comprising:

-   a) determining whether the subject has a c-Met associated cancer;    and-   b) if the subject has a c-Met associated cancer, administering to    the subject an effective amount of a compound of the invention.    In one embodiment, the subject's cancer is determined to be a c-Met    associated cancer if the subject's cancer has one or more mutation    or deletion in the kinase or juxtamembrane domain of c-Met,    amplification of the Met gene, overexpression of c-Met, or a    combination thereof.

E. Agents Useful in Combination with the Compounds of the Invention

Without wishing to be bound by theory, it is believed that the compoundsof the invention can be particularly effective at treating subjectswhose cancer has become multi-drug resistant. Although chemotherapeuticagents initially cause tumor regression, most agents that are currentlyused to treat cancer target only one pathway to tumor progression.Therefore, in many instances, after treatment with one or morechemotherapeutic agents, a tumor develops multidrug resistance and nolonger response positively to treatment. One of the advantages ofinhibiting Hsp90 activity is that several of its client proteins, whichare mostly protein kinases or transcription factors involved in signaltransduction, have been shown to be involved in the progression ofcancer. Thus, inhibition of Hsp90 provides a method of short circuitingseveral pathways for tumor progression simultaneously. Therefore, it isbelieved that treatment of cancer with an Hsp90 inhibitor of theinvention either alone, or in combination with other chemotherapeuticagents, is more likely to result in regression or elimination of thetumor, and less likely to result in the development of more aggressivemultidrug resistant tumors than other currently available therapies.

In addition, the compounds of the invention are useful for treatingpatients with c-Met associated cancers, such as patients with hereditaryand sporadic human papillary renal carcinomas, ovarian cancer,hepatocellular carcinoma, metastatic head and neck squamous cellcarcinomas, esophageal cancer, gastric cancer, non-small cell lungcancer (NSCLC) and small cell lung cancer (SCLC), colorectal cancer, andosteogenic sarcoma. Such c-Met associated cancers may have becomeresistant to treatment with a tyrosine kinas inhibitor, such asGefitinib, Tarceva, Gleevec, or SU11274. Compounds of the invention actby inhibiting the activity of Hsp90 which disrupt c-Met/Hsp90 complexesand causes degradation of c-Met, including c-Met that has a mutation ordeletions that makes it constitutively active. Therefore, compounds ofthe invention are effective in treating c-Met associated cancers thatare resistant to treatment with tyrosine kinase inhibitors. Compounds ofthe invention can be administered alone or with a tyrosine kinaseinhibitor in patients who have a c-Met associated cancer that is notresistant to tyrosine kinase inhibitors or to patients whose cancer hasbecome resistant to tyrosine kinase inhibitors.

Other anticancer agents that can be co-administered with the compoundsof the invention include Taxol™, also referred to as “paclitaxel”, is awell-known anti-cancer drug which acts by enhancing and stabilizingmicrotubule formation, and analogs of Taxol™, such as Taxotere™.Compounds that have the basic taxane skeleton as a common structurefeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferongamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Other examples of anti-cancer agents which act by arresting cells in theG2-M phases due to stabilized microtubules include without limitationthe following marketed drugs and drugs in development:

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilizing or depolymerizing microtubules and which canbe used in combination with the compounds of the invention includewithout limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCB, Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411(Sanofi).

F. Compositions and Methods for Administering Therapies

The present invention provides compositions for the treatment,prophylaxis, and amelioration of proliferative disorders, such ascancer, including c-Met associated cancers. In one embodiment, acomposition for treating a c-Met associated cancer comprises and apharmaceutically acceptable carrier, diluent or excipient and one ormore compound of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition for treating a c-Met associated cancer further comprises oneor more prophylactic or therapeutic agents other than a compound of theinvention. In another embodiment, the composition for treating a c-Metassociated cancer further comprises a one or more prophylactic ortherapeutic anticancer agent other than a compound of the invention.

In one embodiment, a composition of the invention is a pharmaceuticalcomposition or a single unit dosage form. Pharmaceutical compositionsand dosage forms of the invention comprise one or more activeingredients in relative amounts and formulated in such a way that agiven pharmaceutical composition or dosage form can be used to treat orprevent proliferative disorders, such as cancer, including a c-Metassociated cancers. In one embodiment, pharmaceutical compositions anddosage forms for treating a c-Met associated cancer comprises a compoundof formula (I) through (LXXII), or any embodiment thereof, or a compoundshown in Table 5, 6, or 7, or a pharmaceutically acceptable prodrug,salt, solvate, clathrate, hydrate, or prodrug thereof, optionally incombination with one or more additional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

i) Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

ii) Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormula (I) through (LXXII), or any embodiment thereof, or a compoundshown in Table 5, 6, or 7, or a pharmaceutically acceptable salt,solvate, hydrate, clathrate, or prodrug thereof, in spheroids whichfurther comprise microcrystalline cellulose and, optionally,hydroxypropylmethylcellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entirely of whichis incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formula (I) through (LXXII), orany embodiment thereof, or a compound shown in Table 5, 6, or 7, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, by weight, about 50% to about 94% microcrystallinecellulose, NF, by weight, and optionally from about 0.25% to about 1% byweight of hydroxypropylmethylcellulose, USP, wherein the spheroids arecoated with a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

iii) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

iv) Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

v) Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of aproliferative disorders, such as a c-Met associated cancer, or one ormore symptoms thereof, will vary with the nature and severity of thedisease or condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each patient depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thepatient. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems. Suitable regimentscan be selected by one skilled in the art by considering such factorsand by following, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. In another embodiment, the compounds of the invention areadministered one to three times a week. Specifically, a dose rangeshould be from about 5 mg to about 500 mg per day, more specifically,between about 10 mg and about 200 mg per day. In managing the patient,the therapy should be initiated at a lower dose, perhaps about 1 mg toabout 25 mg, and increased if necessary up to about 200 mg to about 1000mg per day as either a single dose or divided doses, depending on thepatient's global response. It may be necessary to use dosages of theactive ingredient outside the ranges disclosed herein in some cases, aswill be apparent to those of ordinary skill in the art. Furthermore, itis noted that the clinician or treating physician will know how and whento interrupt, adjust, or terminate therapy in conjunction withindividual patient response.

Different therapeutically effective amounts may be applicable fordifferent proliferative disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such proliferative disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a proliferative disorders, such as a c-Met associatedcancer, or one or more symptoms thereof in a patient is 150 μg/kg,preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg,50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg ormore of a patient's body weight. In another embodiment, the dosage ofthe composition of the invention or a compound of the inventionadministered to prevent, treat, manage, or ameliorate a proliferativedisorders, such as a c-Met associated cancer, or one or more symptomsthereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg,0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mgto 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg,0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg, 0.5 mg to2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mgto 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) Ed.,2003, Medical Economics Co., Inc., Montvale, N.J., which areincorporated herein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered less than 5 minutesapart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart,at about 1 to about 2 hours apart, at about 2 hours to about 3 hoursapart, at about 3 hours to about 4 hours apart, at about 4 hours toabout 5 hours apart, at about 5 hours to about 6 hours apart, at about 6hours to about 7 hours apart, at about 7 hours to about 8 hours apart,at about 8 hours to about 9 hours apart, at about 9 hours to about 10hours apart, at about 10 hours to about 11 hours apart, at about 11hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96hours apart, or 96 hours to 120 hours part. In one embodiment, two ormore therapies (e.g., prophylactic or therapeutic agents) areadministered within the same patient visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such asc-Met associated cancer, or one or more symptoms thereof, said methodscomprising administering to a subject in need thereof a dose of at least150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, atleast 150 mg/kg, or at least 200 mg/kg or more of one or more compoundsof the invention once every day, preferably, once every 2 days, onceevery 3 days, once every 4 days, once every 5 days, once every 6 days,once every 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

G. Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

1. EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Example 1 Synthesis of Compound 76

The hydrazide (M) (1.45 g, 7.39 mmol) and the isothiocyanate (N) (1.59g, 7.39 mmol) were dissolved in ethanol (20 ml) with heating. When thestarting materials were dissolved the solution was allowed to cool toroom temperature and a precipitate formed. This precipitate was filteredthen washed with ether to provide the intermediate (P) as a white solid(2.85 g, 97%). The intermediate (VII) (1.89 g, 4.77 mmol) was heated ina solution of sodium hydroxide (0.38 g, 9.54 mmol) in water (20 mL) at110° C. for 2 hours. The solution was allowed to cool to roomtemperature then acidified with conc. HCl. The resulting precipitate wasfiltered then washed with water (100 mL) and dried. The crude productwas recrystallized from ethanol to produce compound 76 as a white solid(1.4 g, 75%).

¹H NMR (DMSO-d₆) δ 9.43-9.53 (bs, 2H), 8.11-8.16 (m, 1H), 7.47-7.55 (m,2H), 7.38 (d, J=8.1 Hz, 1H), 7.31-7.36 (m, 1H), 6.98 (d, J=8.1 Hz, 1H),6.71 (s, 1H), 6.17 (s, 1H), 3.98 (s, 3H), 2.17 (q, J=7.5 Hz, 2H), 0.73(t, J=7.5 Hz, 3H);

ESMS calculated for (C₂₁H₁₉N₃O₃S) 393.11. Found 394.1 (M+1)⁺.

Example 2 Synthesis of Compound 124

3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole (505mg, 1.5 mmol), which is commercially available from Scientific Exchange,Inc., Center Ossipee, N.H. 03814, and Et₃N (0.84 ml, 6.0 mmol) in 15 mlCH₂Cl₂ were treated dropwise with ethyl isocyanate (360 mg, 5.0 mmol) at0° C. The mixture was then warmed to room temperature and stirred for 3h. The reaction mixture was diluted with CH₂Cl₂, washed with H₂O andsaturated brine, dried with Na₂SO₄, and concentrated in vacuo. Theresidue was chromatographed (Hexane/EtOAc 3:1) to give Compound 124 as awhite solid (480 mg, 58%).

¹H-NMR (CDCl₃) δ 10.13 (s, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.61-7.57 (m,3H), 7.49-7.36(m, 2H), 7.01(s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.70 (d,J=8.4 Hz, 1H), 4.98-4.96(m, 2H), 3.56(q, J=7.2 Hz, J=12.6 Hz, 2H),3.28-3.10(m, 4H), 1.33(t, J=7.2 Hz, 3H), 1.13 (q, J=15.0 Hz, J=7.2 Hz,6H);

ESMS calculated for C₂H₂₈N₆O₅S: 548.18. Found: 549.1 (M+1)⁺.

Example 3 Synthesis of Compound 188

1-Benzenesulfonyl-7-methoxy-1H-indole (Q)

To a solution of 7-methoxyindole (1 eq) in DMF cooled in an ice bath wasadded NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for1 hr at room temperature then recooled in an ice bath. Benzenesulfonylchloride (1.1 eq) was added then the reaction was stirred for 2 hrs atroom temperature. Water/ethyl acetate were added and the ethyl acetatelayer was washed repeatedly (3×) with water. The ethyl acetate layer wasconcentrated and evaporated to dryness.

1-Benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R)

To a solution of 1-benzenesulfonyl-7-methoxy-1H-indole (Q) (1 eq) indichloromethane cooled in an ice bath was added SiO₂—HNO₃ (2 wt eq) insmall portions. The reaction was stirred for 1 hr at room temperature.Activated carbon (2 wt eq) was added then the entire mixture was stirredfor 1 hr. The mixture was then filtered and evaporated to dryness.Separation of the isomers was achieved by column chromatography.

7-Methoxy-4-nitro-1H-indole (S)

To a solution of 1-benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R) (1eq) in methanol was added a solution of sodium hydroxide (5 eq) inwater. The solution was heated to reflux for 3 hrs. Methanol was removedunder reduced pressure then water and ethyl acetate were added. Theethyl acetate layer separated and washed repeatedly (3×) with water. Theethyl acetate layer was concentrated and evaporated to dryness toproduce the desired product.

1-Isopropyl-7-methoxy-4-nitro-1H-indole (T)

To a solution of 7-methoxy-4-nitro-1H-indole (S) (1 eq) in DMF cooled inan ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reactionwas stirred for 1 hr at room temperature then recooled in an ice bath.2-Iodopropane (1.1 eq) was added then the reaction was stirred for 2 hrsat room temperature. Water and ethyl acetate were added. The ethylacetate layer was separated and washed repeatedly (3×) with water. Theethyl acetate layer was concentrated then evaporated to dryness. Furtherpurification by column chromatography produced the pure desired product.

1-Isopropyl-7-methoxy-1H-indol-4-ylamine (U)

A solution of 1-isopropyl-7-methoxy-4-nitro-1H-indole (T) (1 eq) andpalladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate(1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for 1hr. The reaction was then filtered through Celite and evaporated todryness to produce the desired product.

1-Isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V)

To a solution of 1-isopropyl-7-methoxy-1H-indol-4-ylamine (U) (1 eq) indichloromethane was added 1,1′-thiocarbonyldiimidazole (1.2 eq). Thereaction was stirred for 2 hrs at room temperature then evaporated todryness. Further purification by column chromatography produced the puredesired product.

3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole(Compound 188)

5-Ethyl-2,4-dihydroxy-benzoic acid hydrazide (W) (1 eq) and1-isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V) (1.01 eq) wereheated in ethanol (0.02 M based on isothiocyante) at 80° C. for 1 hr.The solution was allowed to cool to room temperature overnight. Theresulting precipitate was filtered, washed with ether, dried and usedwithout further purification (yield 80%). The precipitate was suspendedin aqueous NaOH solution (2 eq NaOH) and nitrogen was bubbled throughthis suspension for 10 min. The reaction was then heated to 110° C. for1 hr under a nitrogen atmosphere then allowed to cool to roomtemperature. Neutralisation with conc. HCl produced a white precipiatewhich was filtered and washed with water. Repeated recrystallisationfrom EtOH/water produced the desired product (purity>95%, yield 50-70%)

¹H-NMR (DMSO-d₆) δ (ppm), 9.52 (s, 1H), 9.42 (s, 1H), 7.40 (d, J=3.3 Hz,1H), 6.82 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 6.05 (d, J=3.3Hz, 1H), 5.30 (qn, J=6.6 Hz, 1H), 3.89 (s, 3H), 2.14 (q, J=7.5 Hz, 2H),1.41-1.47 (m, 6H), 0.68 (t, J=7.5 Hz, 3H);

2. ESMS Calculated. for C₂₂H₂₄N₄O₃S: 424.16. Found: 425.1 (M+1)⁺ Example4 Synthesis of Compound 223

2,4-Dimethoxy-5-isopropylbenzoic acid (2.24 g, 10.0 mmol, 1.00 equiv.)in 50 mL CH₂Cl₂ at room temperature was treated with (COCl)₂ (1.40 g,11.0 mmol, 1.10 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour.Solvent and excess (COCl)₂ were removed in vacuo. The residue wasdissolved in 100 mL CH₂Cl₂, and treated with 1,3-dimethyl-5-aminoindole(1.60 g, 10.0 mmol, 1.00 equiv.) and triethylamine (1.55 g, 15.0 mmol,1.50 equiv.) at 0° C. for one hour. Aqueous workup and removal ofsolvent gave a light brown solid which was washed with ether to yieldoff-white solid (2.28 g, 6.22 mmol, 62%).

¹H NMR (CDCl₃) δ (ppm) 9.78 (br s, 1H), 8.21 (s, 1H), 8.09 (d, J=2.1 Hz,1H), 7.31 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.82 (s,1H), 6.50 (s, 1H), 4.09 (s, 3H), 3.92 (s, 3H), 3.73 (s, 3H), 3.26 (hept,J=6.9 Hz, 1H), 2.32 (s, 3H), 1.24 (d, J=6.9 Hz, 6H).

The off-white solid obtained above was treated with Lawesson's reagent(1.51 g, 3.74 mmol, 0.6 equiv.) in 50 mL toluene at 110° C. for threehours. Toluene was removed on rotary evaporator and vacuum pump, and theresidue was treated with hydrazine (anhydrous, 3.0 g, 94 mmol, 15.0equiv.) in 20 mL dioxane at 80° C. for 30 minutes. The reaction mixturewas extracted with ethyl acetate and water to remove excess hydrazine.The organic layer was dried over MgSO₄, and filtered to remove dryingagent. Carbodiimidazole (CDI)(3.02 g, 18.7 mmol, 3.00 equiv.) was addedto the solution, and the solution was refluxed (65° C.) for 2 hours.Solvent was removed, and the residue was treated with 20 mL THF and 10mL NaOH (2M) to destroy excess CDI. Extraction with ethyl acetate(EtOAc) and water, followed by chromatography purification gave thedesired product3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazoleas light brown solid (2.20 g, 5.42 mmol, 87%).

¹H NMR (CDCl₃), δ (ppm) 9.63 (br s, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.20(s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.80(s, 1H), 6.19 (s, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.40 (s, 3H), 3.15(hept, J=6.9 Hz, 1H), 2.20 (s, 3H), 1.10 (d, J=6.9 Hz, 6H).

3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazoleobtained above was treated with pyridine hydrochloride (12.53 g, 108.3mmol, 20.0 equiv.), NaI (0.812 g, 5.42 mmol, 1.0 equiv.) and 0.5 mLwater at 205° C. under nitrogen protection for 1 hour. The reactionmixture was treated with 200 mL water. The solid was collected byfiltration, washed with 3×20 mL water, and dissolved in 50 mL 2M NaOHsolution. The aqueous solution was extracted with 100 mL EtOAc, and theEtOAc layer was extracted with 2×20 mL 0.5M NaOH. EtOAc layer wasdiscarded. The aqueous layer were combined, neutralized with HCl to PHaround 5, and extracted with 3×100 mL EtOAc. The combined EtOAc layerwas diluted with 50 mL THF, dried over MgSO₄, and filtered throughsilica gel plug. Most of solvents were removed to form a slurry witharound 2 mL of solvent left. Solid was collected by filtration, washedwith 2 mL EtOAc, and dried. The desired product3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole(Compound 223) was obtained as an off-white solid (1.75 g, 4.63 mmol,85%).

¹H NMR (CD₃OD), δ (ppm) 7.46 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H),7.04 (dd, J=8.4 Hz, 1.8 Hz, 1H), 7.02 (s, 1H), 6.53 (s, 1H), 6.26 (s,1H), 3.74 (s, 3H), 2.88 (sept, J=6.9 Hz, 1H), 2.24 (s, 3H), 0.62 (d,J=6.9 Hz, 6H);

ESMS calculated. for C₂₁H₂₃N₄O₃ 378.1. Found: 379.1 (M+1)⁺.

The following compounds were prepared as described above in the sectionentitled “Methods of Making the Compounds of the Invention” and asexemplified in Examples 1 through 4.

Example 5 Compound 1

ESMS calcd for C₁₈H₁₃N₃OS: 319.1. Found: 320.0 (M+1)⁺.

Example 6 Compound 2

ESMS calcd for C₂₁H₁₉N₃O₄S: 409.11. Found: 410.0 (M+H)⁺.

Example 7 Compound 5

ESMS calcd for C₁₉H₁₅N₃O₂S: 365.08. Found: 266.0 (M+H)⁺.

Example 8 Compound 6

ESMS calcd for C₂₀H₁₇N₃O₂S: 379.10. Found: 380.0 (M+H)⁺.

Example 9 Compound 7

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11. Found: 394.0 (M+H)⁺.

Example 10 Compound 8

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0(M+H)⁺.

Example 11 Compound 9

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11. Found: 394.0 (M+H)⁺.

Example 12 Compound 13

¹H-NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.57 (s, 1H), 7.50 (d, J=8.1 Hz, 1H),7.35 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H),6.88 (d, J=8.1 Hz, 1H), 6.09-6.11 (m, 2H), 6.01 (dd, J₁=2.1 Hz, J₂=8.1Hz, 1H), 4.13-4.22 (m, 2H), 1.36 (t, J=7.2 Hz, 3H);

ESMS calcd for C₁₈H₁₆N₄O₂S: 352.10. Found: 353.1 (M+1)⁺.

Example 13 Compound 14

¹H NMR (DMSO-d₆) δ 9.72(s, 1H), 9.67(s, 1H), 7.04-7.01(m, 1H),6.83-6.78(m, 2H), 6.66-6.63(m, 1H), 6.20-6.19(m, 2H), 4.22(s, 4H);

ESMS calcd for C₁₆H₁₃N₃O₄S: 343.06. Found: 344.0 (M+1)⁺.

Example 14 Compound 15

ESMS calcd for C₁₅H₁₃N₃O₂S: 299.07. Found: 300.0 (M+H)⁺.

Example 15 Compound 16

ESMS calcd for C₁₅H₁₃N₃O₂S: 299.07. Found: 300.0 (M+H)⁺.

Example 16 Compound 17

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02. Found: 320.0 (M+H)⁺.

Example 17 Compound 18

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02. Found: 320.0 (M+H)⁺.

Example 18 Compound 19

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02. Found: 320.1 (M+H)⁺.

Example 19 Compound 20

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07. Found: 316.0 (M+H)⁺.

Example 20 Compound 21

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07. Found: 316.0 (M+H)⁺.

Example 21 Compound 22

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07. Found: 316.0 (M+H)⁺.

Example 22 Compound 23

ESMS calcd for C₁₄H₁₀FN₃O₂S: 303.05. Found: 304.0 (M+H)⁺.

Example 23 Compound 23

¹H NMR (DMSO-d₆) δ 9.69 (s, 1H), 9.65 (s, 1H), 7.16 (d, J=7.2 Hz, 1H),7.05 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.1 Hz, 2H), 6.11-6.16 (m, 2H), 2.21(s, 3H), 1.89 (s, 3H);

ESMS Calcd C₁₆H₁₅N₃O₂S: 313.09. Found 314.1 (M+1)⁺.

Example 24 Compound 24

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09. Found: 314.0 (M+H)⁺.

Example 25 Compound 25

¹H NMR (DMSO-d₆) δ 10.44 (m, 1H), 8.00-7.95 (m, 2H), 7.55-7.37 (m, 5H),6.61 (d, J=7.8 and 1.8 Hz, 1H), 6.51 (t, J=8.6 Hz, 1H), 6.41 (d, J=10.8Hz, 1H);

ESMS calcd for C₁₈H₁₂FN₃OS: 337.07. Found: 338.0 (M+1)⁺.

Example 26 Compound 26

¹H NMR (DMSO-d₆) δ 9.57 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.96 (d, J=6.9Hz, 1H), 7.55-7.37 (m, 5H), 6.61 (d, J=8.1 Hz, 1H), 5.83 (d, J=2.1 Hz,1H), 5.73(dd, J=8.1 and 1.8 Hz, 1H), 5.24 (s, 2H);

ESMS calcd for C₁₈H₁₄N₄OS: 334.09. Found: 335.0 (M+1)⁺.

Example 27 Compound 27

ESMS calcd for C₁₈H₁₉N₃O₂S: 341.12. Found: 342.0 (M+H)⁺.

Example 28 Compound 28

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09. Found: 314.0 (M+H)⁺.

Example 29 Compound 29

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09. Found: 314.0 (M+H)⁺.

Example 30 Compound 30

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09. Found: 314.0 (M+H)⁺.

Example 31 Compound 31

ESMS calcd for C₁₄H₁₀FN₃O₂S: 303.05. Found: 304.0 (M+H)⁺.

Example 32 Compound 32

ESMS calcd for C₁₅H₁₃N₃O₂S: 331.04. Found: 332.0 (M+H)⁺.

Example 33 Compound 33

ESMS calcd for C₁₈H₁₃N₃O₂S: 335.07. Found: 336.0 (M+H)⁺.

Example 34 Compound 34

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09. Found: 314.0 (M+H)⁺.

Example 35 Compound 35

ESMS calcd for C₁₅H₁₂FN₃O₂S: 317.06. Found: 317.0 (M+H)⁺.

Example 36 Compound 36

ESMS calcd for C20H15N3O2S: 361.1. Found: 362.0 (M+1)⁺.

Example 37 Compound 37

¹H NMR (DMSO-d₆) δ 10.03 (s, 1H), 8.00-7.96 (m, 2H), 7.55-7.37 (m, 5H),7.00 (d, J=8.1 Hz, 1H), 6.20 (m, 2H), 3.57 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09. Found: 350.0 (M+1)⁺.

Example 38 Compound 38

ESMS calcd for C₁₄H₉Cl₂N₃O₂S: 352.98. Found: 353.9 (M+H)⁺.

Example 39 Compound 39

¹H NMR (DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.14 (m, 1H), 7.52-7.48(m, 2H), 7.37 (d, J=8.4 Hz, 1H), 7.32 (m, 1H), 6.96 (d, =8.1 Hz, 1H),6.90 (d, =8.4 Hz, 1H), 6.08 (d, =1.9 Hz, 1H), 6.01 (d, =8.4 Hz, 1H),3.98 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08. Found: 366.0 (M+1)⁺.

Example 40 Compound 40

ESMS calcd for C₂₅H₁₆N₃O₂S: 409.09. Found: 410.0 (M+1)⁺.

Example 41 Compound 42

¹H NMR (DMSO-d₆) δ 9.75 (s, 1H), 9.67(s, 1H), 7.08(s, 2H), 6.96-6.94(m,2H), 6.18-6.13(m, 2H), 2.72-2.50(m, 3H), 2.35-2.28(m, 1H), 1.64-1.60(m,4H);

ESMS calcd for C₁₈H₁₇N₃O₂S: 339.10. Found: 340.0 (M+1)⁺.

Example 42 Compound 43

ESMS calcd for C₂₂H₁₅N₃O₂S: 385.09. Found: 386.0 (M+1)⁺.

Example 43 Compound 44

ESMS calcd for C₂₀H₁₅N₃O₂S: 361.09. Found: 362.0 (M+1)⁺.

Example 44 Compound 45

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09. Found: 350.0 (M+1)⁺.

Example 45 Compound 46

ESMS calcd for C₁₉H₂₁N₃O₃S: 371.13. Found: 372.0 (M+1)⁺.

Example 46 Compound 47

ESMS calcd for C₂₂H₂₇N₃O₃S: 413.18. Found: 414.1 (M+1)⁺.

Example 47 Compound 48

ESMS calcd for C₁₈H₁₂ClN₃O₂S: 369.03. Found: 370.0 (M+H)⁺.

Example 48 Compound 49

¹H NMR (DMSO-d₆) δ 9.49 (s, 1H), 9.40 (s, 1H), 7.94-7.99 (m, 2H),7.38-7.56 (m, 5H), 6.70 (s, 1H), 6.13 (s, 1H), 2.12 (q, J=7.2 Hz, 2H),0.71 (t, J=7.2 Hz, 3H);

ESMS Calcd for C₂₀H₁₇N₃O₂S: 363.10. Found 364.1 (M+1)⁺.

Example 49 Compound 50

ESMS calcd for C₂₀H₁₅N₃O₅S: 409.07. Found: 410.0 (M+H)⁺.

Example 50 Compound 51

ESMS calcd for C₁₈H₁₄N₄O₂S: 350.08. Found: 351.0 (M+H)⁺.

Example 51 Compound 52

ESMS calcd for C₁₇H₁₂N₄OS: 320.07. Found: 320.9 (M+H)⁺.

Example 52 Compound 53

¹H NMR (CDCl₃) δ 12.0 (br s, 1H), 9.87 (br s, 1H), 9.83 (br s, 1H), 7.97(d, J=8.1 Hz, 2H), 7.41-7.56 (m, 5H), 7.13 (d, J=1.5 Hz, 1H), 7.07 (d,J=8.7 Hz, 1H), 6.71 (dd, J=1.8 Hz, 8.1 Hz, 1H), 1.93 (s, 3H);

ESMS calcd for C₂₀H₁₇N₄O₂S: 376.1. Found: 377.0 (M+1)⁺.

Example 53 Compound 56

ESMS calcd for C₁₆H₁₅N₃O₄S: 345.08. Found: 346.0 (M+1)⁺.

Example 54 Compound 57

ESMS calcd for C₁₈H₁₆N₄O₂S: 352.10. Found: 353.0 (M+1)⁺.

Example 55 Compound 61

¹H NMR (DMSO-d₆) δ 9.66(s, 1H), 9.60(s, 1H), 7.29-7.27(m, 1H),7.12-7-10(m, 2H), 7.03-7.00(m, 1H), 6.19-6.17(m, 2H), 1.18(s, 18H);

ESMS calcd for C₂₂H₂₇N₃O₂S: 397.18. Found: 398.1 (M+1)⁺.

Example 56 Compound 64

ESMS calcd for C₂₁H₁₅N₃O₃S: 389.08. Found: 390.0 (M+H)⁺.

Example 57 Compound 65

ESMS calcd for C₁₉H₁₃N₃O₄S: 379.06. Found: 380.0 (M+1)⁺.

Example 58 Compound 66

ESMS calcd for C₂₁H₁₈N₄O₃S: 406.11. Found: 407.0 (M+1)⁺.

Example 59 Compound 67

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+1)⁺.

Example 60 Compound 68

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+1)⁺.

Example 61 Compound 69

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+1)⁺.

Example 62 Compound 70

ESMS calcd for C₁₇H₁₂N₄O₂S: 336.07. Found: 337.0 (M+H)⁺.

Example 63 Compound 71

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+1)⁺.

Example 64 Compound 72

¹H NMR (DMSO-d₆) δ 10.3 (br s, 1H), 7.95-8.19 (m, 2H), 7.48-7.72 (m,5H), 7.17 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 5.95 (d, J=2.1 Hz,1H), 5.73 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.47 (br s, 1H), 3.62 (s, 3H);

ESMS calcd for C₁₉H₁₇N₄O₂S₂: 412.1. Found: 413.0 (M+1)⁺.

Example 65 Compound 73

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.94 (s, 1H), 7.94-7.98 (m, 2H),7.43-7.60 (m, 5H), 5.97 (s, 1H), 1.85 (s, 3H), 1.81 (s, 3H);

ESMS calcd for C₂₀H₁₈N₃O₂S: 363.1. Found: 364.0 (M+1)⁺.

Example 66 Compound 74

ESMS calcd for C₂₁H₁₉N₃O₄S: 409.11. Found: 410.0 (M+H)⁺.

Example 67 Compound 75

¹H NMR (DMSO-d₆) δ 9.46 (s, 1H), 9.45 (s, 1H), 7.95-8.00 (m, 2H),7.38-7.56 (m, 5H), 6.65 (s, 1H), 6.15 (s, 1H), 2.07-2.14 (m, 2H),081-1.18 (m, 11H);

ESMS calcd for C₂₄H₂₆N₃O₂S: 419.1. Found: 420.1 (M+1)⁺.

Example 68 Compound 76

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+H)⁺.

Example 69 Compound 77

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11. Found: 394.0 (M+H)⁺.

Example 70 Compound 78

¹H NMR (DMSO-d₆) δ 9.71 (s, 1H), 9.35 (s, 1H), 7.98-8.04 (m, 2H),7.50-7.62 (m, 5H), 6.58 (s, 1H), 2.15 (q, J=7.5 Hz, 2H), 0.58 (t, J=7.5Hz, 3H);

ESMS calcd for C₂₀H₁₇C1N₃O₂S: 397.0. Found: 398.0 (M+1)⁺.

Example 71 Compound 79

ESMS calcd for C₁₉H₂₁N₃O₃S: 371.13. Found: 372.0 (M+H)⁺.

Example 72 Compound 80

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11. Found: 394.0 (M+H)⁺.

Example 73 Compound 81

ESMS calcd for C₂₀H₁₇N₃O₂S: 379.10. Found: 380.0 (M+H)⁺.

Example 74 Compound 82

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11. Found: 394.0 (M+H)⁺.

Example 75 Compound 83

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10. Found: 380.0 (M+H)⁺.

Example 76 Compound 84

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10. Found: 380.0 (M+H)⁺.

Example 77 Compound 85

ESMS calcd for C₁₉H₁₅N₃O₂S: 365.08. Found: 266.0 (M+H)⁺.

Example 78 Compound 86

¹H NMR (DMSO-d₆) δ 9.68 (s, 1H), 9.58 (s, 1H), 8.2 (dd, J=7.0 and 2.4Hz, 1H), 7.50 (m, 2H), 7.40 (tr, J=8.1 Hz, 1H), 7.32 (m, 1H), 6.97 (d,J=7.5 Hz, 1H), 6.95 (m, 1H), 6.89 (d, =8.4 Hz, 1H), 6.08 (d, =2.1 Hz,1H), 6.0 (dd, =7.4 and 2.1 Hz, 1H), 3.96 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08. Found: 366.0 (M+1)⁺.

Example 79 Compound 87

¹H NMR (MeOH-d₄) δ 8.25 (m, 1H), 7.96 (s, 1H), 7.46-7.44 (m, 2H), 7.26(d, J=8.4 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.17(d, J=2.1 Hz, 1H), 5.98 (dd, J=8.4 and 2.4 Hz, 1H);

ESMS calcd for C₁₈H₁₃N₃O₃S: 351.07. Found: 352.0 (M+1)⁺.

Example 80 Compound 88

¹H-NMR (DMSO-d₆) δ 9.69 (s, 1H), 9.59 (s, 1H), 7.54 (d, J=8.1 Hz, 1H),7.46 (d, J=3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H),6.89 (d, J=8.7 Hz, 1H), 6.12-6.13 (m, 2H), 6.02 (dd, J₁=2.4 Hz, J₂=8.4Hz, 1H), 4.74 (qn, J=6.6 Hz, 1H), 1.40-1.46 (m, 6H);

ESMS calcd for C₁₉H₁₈N₄O₂S: 366.12. Found: 367.1 (M+1)⁺.

Example 81 Compound 89

ESMS calcd for C₂₂H₂₁N₃O₂S: 391.14. Found: 392.0 (M+H)⁺.

Example 82 Compound 90

¹H NMR (DMSO-d₆) δ 9.47 (s, 1H), 9.43 (s, 1H), 7.94-8.00 (m, 2H),7.39-7.57 (m, 5H), 6.68 (s, 1H), 6.15 (s, 1H), 2.05-2.15 (m, 2H),1.05-1.17 (m, 2H), 0.50 (t, J=7.5 Hz, 3H); ESMS calcd for C₂₁H₂₀N₃O₂S:377.1. Found: 378.0 (M+1)⁺.

Example 83 Compound 91

¹H NMR (DMSO-d₆) δ 9.15 (s, 1H), 8.50 (s, 1H), 8.00-8.07 (m, 2H),7.47-7.63 (m, 5H), 6.27 (s, 1H), 2.06 (q, J=7.5 Hz, 2H), 1.93 (s, 3H),0.45 (t, J=7.5 Hz, 3H);

ESMS calcd for C₂₁H₂₀N₃O₂S: 377.1. Found: 378.0 (M+1)⁺.

Example 84 Compound 93

ESMS calcd for C₁₆H₁₅N₃O₄S: 345.08. Found: 346.0 (M+H)⁺.

Example 85 Compound 95

ESMS calcd for C₁₆H₁₂N₄O₂S: 324.07. Found: 325.0 (M+H)⁺.

Example 86 Compound 96

ESMS calcd for C₁₉H₁₈N₄O₃S: 382.11. Found: 383.0 (M+H)⁺.

Example 87 Compound 98

ESMS calcd for C₁₇H₁₂N₄O₂S: 336.07. Found: 337.0 (M+H)⁺.

Example 88 Compound 99

ESMS calcd for C₁₉H₁₃N₃O₄S: 379.06. Found: 379.9 (M+H)⁺.

Example 89 Compound 100

¹H-NMR (DMSO-d₆) δ 9.52 (s, 1H), 9.42 (s, 1H), 7.56 (d, J=8.7 Hz, 1H),7.49 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),6.61 (s, 1H), 6.21 (s, 1H), 6.14 (dd, J=3.3 Hz, 1H), 4.76 (qn, J=6.6 Hz,1H), 2.14 (q, J=7.5 Hz, 2H), 1.41-1.47 (m, 6H), 0.66 (t, J=7.5 Hz, 3H);

ESMS calcd for C₂₁H₂₂N₄O₂S: 394.15. Found: 395.1 (M+1)⁺.

Example 90 Compound 101

ESMS calcd for C₁₉H₁₇N₅O₃S: 395.11. Found: 396.0 (M+H)⁺.

Example 91 Compound 102

ESMS calcd. for C₁₉H₂₀N₅O₂S: 381.1. Found: 382.0 (M+1)⁺.

Example 92 Compound 103

¹H NMR (DMSO-d₆) δ 9.48 (s, 1H), 9.38 (s, 1H), 7.29(d, J=8.4 Hz, 1H),7.25(d, J=1.8 Hz, 1H), 6.85-6.89 (m, 2H), 6.18 (s, 1H), 3.61 (s, 3H),2.30 (s, 3H), 2.29 (q, J=7.5 Hz, 2H), 2.09 (s, 3H), 0.94 (t, J=7.5 Hz,3H);

ESMS calcd for C₂₁H₂₃N₄O₂S: 394.1. Found: 395.0(M+1)⁺.

Example 93 Compound 104

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08. Found: 366.0 (M+H)⁺.

Example 94 Compound 106

ESMS calcd for C₂₀H₁₇N₄O₂S: 377.1. Found: 378.0 (M+H)⁺.

Example 95 Compound 107

ESMS calcd for C₁₈H₁₃ClN₃O₂S: 369.0. Found: 370.0 (M+H)⁺.

Example 96 Compound 116

¹H NMR (DMSO-d₆) δ 7.98-7.56 (m, 2H), 7.55-7.30 (m, 6H), 6.43 (dd, J=8.1and 1.8 Hz, 1H), 6.29 (m, 1H), 3.65 (s, 3H), 3.16 (s, 3H);

ESMS calcd for C₂₀H₁₇N₃O₂S: 363.10. Found: 364.0 (M+1)⁺.

Example 97 Compound 117

¹H-NMR (CDCl₃) δ 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m,1H), 6.99 (d, J=1.8 Hz, 1H), 6.80(d, J=8.7 Hz, 1H), 6.62-6.58(m, 1H),2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.81(s, 3H), 2.75-2.69(m, 6H);

ESMS calcd for C₂₇H₂₈N₆O₅S: 548.18. Found: 549.2 (M+1)⁺.

Example 98 Compound 122

¹H-NMR (CDCl₃) δ 7.98(m, 2H), 7.60-7.55(m, 3H), 7.51-7.45(m, 1H),7.36-7.33(m, 1H), 6.98-6.97(m, 1H), 6.86(d, J=9.9 Hz, 1H), 6.70-6.67(m,1H), 2.86(s, 3H), 2.26(s, 3H), 2.21(s, 3H);

ESMS calcd for C₂₄H₁₉N₃O₅S: 461.10. Found: 462.0 (M+1)⁺.

Example 99 Compound 125

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10. Found: 380.0 (M+H)⁺.

Example 100 Compound 126

ESMS calcd for C₁₀H₁₁N₃O₂S: 237.06. Found: 238.0 (M+H)⁺.

Example 101 Compound 127

ESMS calcd for C₁₁H₁₃N₃O₂S: 251.07. Found: 252.0 (M+H)⁺.

Example 102 Compound 128

ESMS calcd for C₁₁H₁₃N₃O₂S: 251.07. Found: 252.0 (M+H)⁺.

Example 103 Compound 129

ESMS calcd for C₁₁H₁₁N₃O₂S: 249.06. Found: 250.0 (M+H)⁺.

Example 104 Compound 130

ESMS calcd for C₁₂H₁₅N₃O₂S: 265.09. Found: 266.0 (M+H)⁺.

Example 105 Compound 131

ESMS calcd for C₂₀H₁₅N₃O₄S: 393.08. Found: 394.1 (M+H)⁺.

Example 106 Compound 177

¹H NMR (DMSO-d₆) δ 9.34(s, 1H), 9.22(s, 1H), 8.01-7.96 (m, 2H),7.58-7.44 (m,

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08. Found: 366.0 (M+1)⁺.

Example 107 Compound 178

¹H NMR (DMSO-d₆) δ 10.29 (s, 1H), 9.49 (s, 1H), 9.42 (s, 1H), 8.16 (t,J=5.1 Hz, 1H), 7.45-7.43 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.84 (d, J=7.8Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 2.12 (q,J=7.5 Hz, 2H), 0.70 (t, J=7.2 Hz, 3H);

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10. Found: 379.9 (M+1)⁺.

Example 108 Compound 179

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09. Found: 350.0 (M+1)⁺.

Example 109 Compound 180

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09. Found: 350.0 (M+H)⁺.

Example 110 Compound 181

ESMS calcd for C20H15N3O2S: 361.09. Found: 362.0 (M+H)⁺.

Example 111 Compound 182

ESMS calcd for C₁₆H₁₅N₃O₃S: 329.08. Found: 330.0 (M+H)⁺.

Example 112 Compound 183

ESMS calcd for C₂₀H₁₇N₃O₂S: 363.10. Found: 364.0 (M+H)⁺.

Example 113 Compound 184

ESMS calcd for C₁₈H₁₃N₃O₃S: 350.38. Found: 351.9 (M+H)⁺.

Example 114 Compound 185

ESMS calcd. for C₂₀H₂₁N₄O₂S: 380.1. Found: 381.0 (M+1)⁺.

Example 115 Compound 187

3. ESMS calcd. for C₁₉H₂₀N₅O₂S: 381.1. Found: 382.0 (M+1)⁺.

Example 116 Compound 190 4. ESMS Calcd. for C₂₁H₂₂N₄O₂S: 394.15. FOUND:395.0 (M+1)⁺. Example 117 Compound 191

ESMS calcd. for C₂₂H₂₃N₄O₄S: 438.1. Found: 439.0 (M+1)⁺.

Example 118 Compound 192

ESMS calcd. for C₂₀H₂₂N₅O₂S: 395.1. Found: 396.0 (M+1)⁺.

Example 119 Compound 193

ESMS calcd. for C₂₀H₂₂N₅O₂S: 395.1. Found: 396.0 (M+1)⁺.

Example 120 Compound 194

ESMS calcd. for C₂₃H₂₇N₄O₂S: 422.1. Found: 423.0 (M+1)⁺.

Example 121 Compound 195

ESMS calcd. for C₂₃H₂₅N₄O₂S: 420.1. Found: 421.0 (M+1)⁺.

Example 122 Compound 196

ESMS calcd. for C₂₅H₂₉N₄O₂S: 448.1. Found: 449.3 (M+1)⁺.

Example 123 Compound 197

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.16. Found: 409.2 (M+1)⁺.

Example 124 Compound 198

ESMS calcd. for C₂₃H₂₆N₄O₂S: 422.18. Found: 423.3 (M+1)⁺.

Example 125 Compound 199

ESMS calcd. for C₂₄H₂₈N₄O₂S: 436.19. Found: 437.3 (M+1)⁺.

Example 126 Compound 200

ESMS calcd. for C₂₂H₂₂N₄O₂S: .406.15. Found: 407.2 (M+1)⁺.

Example 127 Compound 201

ESMS calcd. for C₂₃H₂₄N₄O₃S: 436.16. Found: 437.3 (M+1)⁺.

Example 128 Compound 202

ESMS calcd. for C₂₂H₂₃N₄O₂S: 406.1. Found: 407.0 (M+H)⁺.

Example 129 Compound 204

ESMS calcd. for C₂₄H₂₈N₄O₃S: .452.19. Found: 453.2 (M+1)⁺.

Example 130 Compound 205

ESMS calcd. for C₂₃H₂₄N₄O₃S: 436.16. Found: 437.1 (M+1)⁺.

Example 131 Compound 206

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1. Found: 395.1 (M+1)⁺.

Example 132 Compound 207

ESMS calcd. for C₂₀H₂₁N₄O₂S: 380.1. Found: 381.1 (M+1)⁺.

Example 133 Compound 208

ESMS calcd. for C₂₃H₂₆N₄O₃S: 438.17. Found: 439.1 (M+1)⁺.

Example 134 Compound 209

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.1. Found: 409.1 (M+1)⁺.

Example 135 Compound 210

ESMS calcd. for C₂₄H₂₃N₄O₂S: 430.1. Found: 431.1 (M+1)⁺.

Example 136 Compound 211

ESMS calcd. for C₂₁H₂₂N₄O₃S: 410.14. Found: 411.1 (M+1)⁺.

Example 137 Compound 212

ESMS calcd. for C₂₃H₂₆N₄O₃S: 438.17. Found: 439.1 (M+1)⁺.

Example 138 Compound 213

ESMS calcd. for C₂₀H₂)N₄O₂S: 380.1. Found: 381.1 (M+1)⁺.

Example 139 Compound 214

ESMS calcd. for C₁₉H₁₉N₄O₂S: 366.1. Found: 367.1 (M+1)⁺.

Example 140 Compound 215

ESMS calcd. for C₂₀H₁₉N₃O₄S: 397.1. Found: 398.1 (M+1)⁺.

Example 141 Compound 216

¹H NMR (DMSO-d₆): δ (ppm) 9.56 (s, 1H), 9.40 (s, 1H), 8.03 (d, J=2.4 Hz,1H), 7.58 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.4,2.1 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.89 (s, 1H), 6.17 (s, 1H), 2.23(q, J=7.2 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H);

ESMS calcd. for C₁₈H₁₅N₃O₃S: 353.08. Found: 354.0 (M+1)⁺.

Example 142 Compound 217

¹H NMR (DMSO-d₆): δ (ppm) 9.59 (s, 1H), 9.43 (s, 1H), 7.67 (d, J=8.7 Hz,1H), 7.54 (d, J=2.1 Hz, 1H), 7.20 (dd, J=8.4, 2.1 Hz, 1H), 6.96 (s, 1H),6.18 (s, 1H), 2.60 (s, 3H), 2.34 (q, J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz,3H);

ESMS calcd. for C₁₈H₁₆N₄O₃S: 368.09. Found: 369.0 (M+1)⁺.

Example 143 Compound 218

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1. Found: 395.1 (M+1)⁺.

Example 144 Compound 219

ESMS calcd. for C₂₁H₂₁N₄O₂S: 392.1. Found: 393.1 (M+1)⁺.

Example 145 Compound 220

ESMS calcd. for C₂₀H₂₁N₄O₃: 364.1. Found: 365.1 (M+1)⁺.

Example 146 Compound 221

ESMS calcd. for C₂₀H₂₁N₄O₂S: 379.1. Found: 381.1 (M+1)⁺.

Example 147 Compound 222

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1. Found: 395.1 (M+1)⁺.

Example 148 Compound 224

ESMS calcd. for C₁₉H₂₁N₄O₂S: 368.1. Found: 369.1 (M+1)⁺.

Example 149 Compound 225

ESMS calcd. for C₁₉H₁₉N₄O₂S: 366.1. Found: 367.1(M+1)⁺.

Example 150 Compound 226

ESMS calcd. for C₂₀H₂₁N₄O₃: 364.1. Found: 365.1 (M+1)⁺.

Example 151 Compound 227

ESMS calcd. for C₂₁H₂₂N₄O₂S: 394.15. Found: 395.1 (M+1)⁺.

Example 152 Compound 228

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.16. Found: 409.1 (M+1)⁺.

Example 153 Compound 229

ESMS calcd. for C₂₀H₁₈F₃N₅O₂S: 449.11. Found: 450.1 (M+1)⁺.

Example 154 Compound 230

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13. Found: 382.1 (M+1)⁺.

Example 155 Compound 231

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13. Found: 382.1 (M+1)⁺.

Example 156 Compound 232

ESMS calcd. for C₂₂H₂₄N₄O₃S: 392.18. Found: 393.1 (M+1)⁺.

Example 157 Compound 233

ESMS calcd. for C18H17N3O4S: 371.09. Found: 372.1 (M+1)+.

Example 158 Compound 234

ESMS calcd. for C20H21N3O2S: 367.14. Found: 368.1 (M+1)+.

Example 159 Compound 235

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13. Found: 382.1 (M+1)⁺.

Example 160 Compound 239

ESMS clcd for C₁₉H₂₁N₄O₂S: 368.1. Found: 369.1 (M+H)⁺.

Example 161 Compound 240

ESMS clcd for C₁₈H₁₆N₄O₃S: 368.09.10. Found: 369.1 (M+H)⁺.

Example 162 Compound 241

ESMS clcd for C₁₇H₁₅N₅O₃S: 369.09. Found: 370.1 (M+H)⁺.

Example 163 Compound 242

ESMS clcd for C₁₉H₁₈N₄O₃S: 382.11. Found: 383.1 (M+H)⁺.

Example 164 Compound 243

ESMS clcd for C₂₂H₂₆N₄O₃S: 426.17. Found: 427.1 (M+H)⁺.

Example 165 Compound 244

ESMS clcd for C₁₈H₁₆N₄O₄S: 384.09. Found: 385.1 (M+H)⁺

Example 166 Compound 245

ESMS clcd for C₁₈H₁₆N₄O₃S₂: 400.07. Found: 401.1 (M+H)⁺

Example 167 Compound 245

ESMS clcd for C₁₇H₁₄N₄O₃S₂: 386.05. Found: 387.0 (M+H)⁺.

Example 1684-{5-Hydroxy-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol

To a solution of 2,4-dihydroxy-5-isopropylbenzoic acid methyl ester(1.63 g, 7.75 mmol) in dimethylformamide (DMF) (100 mL) was addedpotassium carbonate (3.21 g, 23 mmol) then benzyl chloride (1.95 ml, 17mmol). The suspension was heated to 80° C. for 16 hrs under a nitrogenatmosphere. Ethyl acetate (100 ml) and water (100 ml) were added, andthen the ethyl acetate layer was washed with water (3×50 mL), and thendried over magnesium sulfate, filtered and evaporated to dryness toproduce the desired compound as brown oil (2.9 g, 97%).

2,4-Bis-benzyloxy-5-isopropylbenzoic acid methyl ester (3.23 g, 8.27mmol) and LiOH (1.0 g, 24.8 mmol) were heated in a mixture oftetrahydrofuranyl (THF)/methanol/water (100 mL, 3:1:1) for 16 hrs. Ethylacetate (100 mL) and water (100 ml) were added, then the ethyl acetatelayer was washed with water (3×50 mL), dried over magnesium sulfate,filtered and evaporated to dryness to produce the desired compound as ayellow solid (2.6 g, 83%).

2,4-Bis-benzyloxy-5-isopropylbenzoic acid (1.25 g, 3.32 mmol) wasdissolved in dichloromethane (50 mL) and cooled in an ice bath. Oxalylchloride (0.32 mL, 3.65 mmol) was added followed by the dropwiseaddition of DMF (0.1 mL). The reaction was stirred at room temperaturefor 1 hr then evaporated to dryness under reduced pressure to produce abrown solid. This solid was dissolved in THF (50 mL) and cooled in anice bath. A solution of4-Methoxy-N³-methyl-N³-propyl-benzene-1,3-diamine (0.71 g, 3.65 mmol) inTHF (20 mL) was added dropwisely followed by the triethylamine (1.6 mL)and the reaction was stirred at room temperature for 16 hrs. Ethylacetate (50 mL) and water (100 mL) were added. The ethyl acetate layerwas washed with water (3×50 mL), dried over magnesium sulfate, filteredand evaporated to dryness to produce the crude product as a brown solid.Purification by silicagel chromatography (elution with 25% ethylacetate/hexane) provided the desired compound as a white solid (1.8 g,93%).

2,4-Bis-benzyloxy-5-isopropyl-N-[4-methoxy-3-(methylpropylamino)phenyl]benzamide(700 mg, 1.27 mmol) and Lawesson's reagent (0.31 g, 0.76 mmol) weredissolved in toluene (20 mL) and heated to 110° C. for 3 hrs thenevaporated to dryness under reduced pressure to produce a yellow oil.This crude product was dissolved in dioxane (10 mL), anhydrous hydrazine(0.6 mL) was added and the reaction was heated to 80° C. for 30 min.After cooling, ethyl acetate (50 mL) and water (50 mL) were added. Theethyl acetate layer was washed with water (3×50 mL), dried overmagnesium sulfate, filtered and evaporated to dryness to produce thecrude product as a brown solid. This solid was dissolved in ethylacetate (50 mL), CDI (0.66 g, 4.08 mmol) was added then the reaction washeated to reflux for 3 hrs. Removal of the solvent under reducedpressure followed by purification by silicagel chromatography (elutionwith 50% ethyl acetate/hexane) provided the desired compound as a whitesolid (250 mg, 33% over 3 steps).

5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-ol(240 mg, 0.4 mmol) was dissolved in methanol (10 mL) then 10% palladiumon charcoal (200 mg) was added and the reaction was stirred under anatmosphere of hydrogen for 16 hrs. Filtration was carried out through asilca gel plug and removal of the solvent under reduced pressureproduced the desired compound as a white solid (150 mg, 94%).

¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 11.8 (s, 1H), 9.55 (s, 1H), 9.39 (s,1H), 6.88 (d, J=8.7 Hz, 1H), 6.77-6.79 (m, 2H), 6.5 (s, 1H), 6.24 (s,1H), 3.73 (s, 3H), 2.97 (qn, J=6.9 Hz, 1H), 2.79 (t, J=7.5 Hz, 2H), 2.48(s, 3H), 1.30 (m, 2H), 0.97 (d, J=6.9 Hz, 6H), 0.73 (t, J=7.5 Hz, 3H).

ESMS clcd for C₂₂H₂₈N₄O₄: 412.21. Found: 413.2 (M+H)⁺.

Example 1694-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mLdichloromethane at 0°-5° C. was treated with triethylamine (10.0 g,100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hourand 0.5 h at room temperature (RT). Normal aqueous workup and removal ofsolvent gave a light yellow solid which was washed with hexane/EtOAc(9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2g, 98%).

To a stirred solution of 11.2 g (50.0 mmol) of (2) in 150 mL ofanhydrous THF at 0° C. under the nitrogen, was added 3.0 g (75 mmol) ofNaH (60% in oil). The suspension was stirred for 0.5 h at 0° C. and 10mL (150 mmol) of iodomethane was added at 0° C. After the mixture warmedto room temperature and stirred for 3 h, the reaction was quenched byice brine and extracted with EtOAc (200 mL). The organic phase waswashed with brine, dried (Na₂SO₄), filtered, evaporated in vacuo and thesolid was washed with hexane/EtOAc (9:1) to give pure productN-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) as a light yellowsolid (11.3 g, 95% yield).

N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10.0 g 42 mmol)and borane-methyl sulfide complex (21 mL of 2.0M solution intetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min,cooled and quenched by ice-water (slowly). Extraction with EtOAc and theorganic layer washed with brine dried (Na₂SO₄), filtered and evaporatedin vacuo to give (9.1 g, 96%)(2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil.

A solution of 9.0 g (40.1 mmol) of(2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) in 200 mL ofMeOH/EtOAc (1:1) containing 5% w/w of Pd—C (10%) was subjected tohydrogenation (1 atm, balloon) overnight. The contents of the flask werepassed through a short pad of celite and washed with EtOAc. The filtratewas evaporated under reduced pressure to give 7.7 g (92%) of crude amine4-Methoxy-N3-methyl-N3-propyl-benzene-1,3-diamine (5) of an oil.

To a stirred solution of 6.8 g (35.0 mmol) of (5) in 150 mL of CH₂Cl₂ atRT was added 6.4 g (35 mmol) of 1,1′-thiocarbonyldiimidazole. Themixture was stirred at room temperature for 15 minutes and thenevaporated under reduced pressure and the residue was passed through ashort pad of silica gel, eluting with a gradient of hexane/EtOAc, whichgave (5-Isothiocyanato-2-methoxy-phenyl)-methyl-propyl-amine (6) (7.85g, 95%) as a colorless oil.

To a stirred solution of 4.5 g (19.0 mmol) of the isothiocyanate (6) in60 mL of ethanol was added 4.0 g (19.0 mmol) of the hydrazide (7)portion wise. The resultant mixture was then heated at 70° C. for 1 h,then cooled. Solvent was removed on rotary evaporator and the residuewas treated with hexane/EtoAc (9:1). The white precipitate thus obtainedwas filtered, washed with ether (2×50 mL) and vacuum dried to 7.6 g(90%) of (8) as white solid.

To a solution of 1.36 g (34 mmol) of NaOH in 80 mL of water was added7.5 g (16.8 mmol) of the intermediate (8) portion-wise. After thedissolution of the solid (1-2 min), the flask was flushed with nitrogenand heated to 110° C. for 3 h. The reaction mixture was cooled, anadditional 100 mL of water was added and the whole mixture was acidifiedwith conc. HCl to pH 7. The white precipitate thus obtained wasfiltered, washed with water (3×75 mL) and dried. The crude product wasthen re-dissolved in a mixture of 200 mL of ethyl acetate, dried overanhydrous Na₂SO₄ and passed through a short pad of silica gel with anadditional 150 mL of ethyl acetate as eluent. The filtrates wereconcentrated and crude product was re-precipitated in 3:1 hexane/ethylacetate to give 6.83 g (95%) of4-isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diolas white solid.

¹H NMR (300 MHz, DMSO-d₆), (ppm): 9.58 (s, 1H); 9.39 (s, 1H); 6.92-6.83(m, 3H); 6.56(d, J=1.8 Hz, 1H); 6.23 (s, 1H); 3.74 (s, 3H); 3.0-2.93(m,1H); 2.81(t, J=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d,J=6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H);

ESMS clcd for C₂₂H₂₈N₄O₃S: 428.19. Found: 429.2 (M+H)⁺.

Example 1704-(4-{3-[(2-Dimethylamino-ethyl)-methyl-amino]-4-methoxy-phenyl}-5-mercapto-4H-[1,2,4]triazol-3-yl)-6-isopropyl-benzene-1,3-diol

An oven-dried flask was charged with cesium carbonate (2.28 g, 7 mmol,1.4 eq), Pd(OAc)₂ (79 mg, 0.35 mmol, 0.07 eq), and X-phos (238 mg, 0.5mmol, 0.1 eq) under nitrogen. 2-bromo-1-methoxy-4-nitrobenzene (1.16 g,5 mmol, 1 eq), N¹,N²,N²-trimethylethane-1,2-diamine (613 mg, 6 mmol, 1.2eq) and toluene (20 mL, 0.25 M) were added, and the mixture was heatedto 100° C. with stiffing overnight. The reaction mixture was cooled toroom temperature and concentrated. The crude product was then purifiedby flash chromatography on silica gel to giveN¹-(2-methoxy-5-nitrophenyl)-N¹, N², N²-trimethylethane-1,2-diamine(2)(340 mg, 1.34 mmol, 27%).

A solution of 340 mg of N¹-(2-methoxy-5-nitrophenyl)-N¹, N²,N²-trimethylethane-1,2-diamine (2) in 20 mL of ethanol containing 5% w/wof Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) for 1.5 h.The contents of the flask were passed through a short pad of celite andwashed with MeOH. The filtrate was evaporated under reduced pressure andcrude amine obtained was carried over to the next reaction withoutfurther purification. Thiocarbodiimidazole (260 mg, 1.46 mmol) was addedto the crude amine in dichloromethane (10 mL) at room temperature. Thereaction mixture was stirred at room temperature for 1 h, andconcentrated. The crude product was then purified by flashchromatography on silica gel to giveN¹-(5-isothiocyanato-2-methoxyphenyl)-)-N¹, N²,N²-trimethylethane-1,2-diamine (3) (110 mg, 0.42 mmol, 31%).

To a stirred solution of 110 mg (0.54 mmol) of the isothiocyanate (3) in5 mL of ethanol was added 105 mg (0.54 mmol) of2,4-dihydroxy-5-isopropyl-benzoic acid hydrazide portion wise. Theresultant mixture was then heated at 80° C. for 1 h, and then cooled.Solvent was removed on rotary evaporator and the residue was treatedwith hexane/EtOAc (9:1). The white precipitate thus obtained wasfiltered, washed with ether (2×20 mL) and vacuum dried to crude productas white solid. This solid was added to a solution of 44 mg (1.08 mmol)of NaOH in 5 mL of water portion-wise. After the dissolution of thesolid (1-2 min), the flask was flushed with nitrogen and heated to 110°C. for 1.5 h. The reaction mixture was cooled, an additional 20 mL ofwater was added and the whole mixture was acidified with conc. HCl to pH7. The white precipitate thus obtained was filtered, washed with water(3×20 mL) and dried. The crude product was then re-dissolved in amixture of 20 mL of ethyl acetate, dried over anhydrous Na₂SO₄ andpassed through a short pad of silica gel with an additional 15 mL ofethyl acetate as eluent. The filtrates were concentrated and crudeproduct was re-precipitated in 3:1 hexane/ethyl acetate to give 97 mg of4-(4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol(4) as white solid.

¹H-NMR300 MHz, DMSO-d₆) δ (ppm): 9.80 (s, 1H), 9.62 (br s, 1H), 6.85 (m.3H), 6.63 (m, 1H), 6.41 (s, 1H), 3.78 (s, 3H), 3.06 (m, 2H), 2.97 (q,J=6.9 Hz, 1H), 2.55 (s, 3H), 2.47 (m, 2H), 2.24 (s, 6H), 0.99 (s, 3H),0.97 (s, 3H).

ESMS clcd for C₂₃H₃₁N₅O₃S: 457.21. Found: 458.2 (M+H)⁺.

Example 1714-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[(2-methoxy-ethyl)methylamino]phenyl}-4H-[1,2,4]triazol-3-yl)-benzene-1,3-diol

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.57 (s, 1H), 9.39 (s, 1H), 6.83-6.90(m, 3H), 6.59 (d, J=2.1 Hz, 1H), 6.23 (s, 1H), 3.74 (s, 3H), 3.39 (t,J=6 Hz, 2H), 3.14 (s, 3H), 3.07 (t, J=6 Hz, 2H), 2.96 (qn, J=6.9 Hz,1H), 2.54 (s, 3H), 0.97 (d, J=6.9 Hz, 6H). ESMS clcd for C₂₂H₂₈N₄O₄S:444.18. Found: 445.2 (M+H)⁺.

Example 1724-{4-[3-(Cyclopropylmethylmethylamino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropylbenzene-1,3-diol

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.56 (s, 1H), 9.39 (s, 1H), 6.85-6.90(m, 3H), 6.58 (d, J=2.1 Hz, 1H), 6.23 (s, 1H), 3.76 (s, 3H), 2.96 (qn,J=6.9 Hz, 1H), 2.76 (d, J=6.3 Hz, 2H), 2.57 (s, 3H), 0.99 (d, J=6.9 Hz,6H), 0.58-0.64 (m, 1H), 0.32-0.34 (m, 2H), −0.03-0.01 (m, 2H).

ESMS clcd for C₂₃H₂₈N₄O₃S: 440.19. Found: 441.1 (M+H)⁺.

Example 173N-{4-[3-(5-Ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-phenyl}-N-methyl-acetamide

ESMS clcd for C₁₉H₂₀N₄O₃S: 384.13. Found: 385.1 (M+H)⁺.

Example 174N-Ethyl-N-{5-[3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-2-methoxy-phenyl}-acetamide

ESMS clcd for C₂₁H₂₄N₄O₄S: 428.15. Found: 429.2 (M+H)⁺.

Example 1754-[4-(3-Diethylamino-4-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₂₁H₂₆N₄O₃S: 414.17. Found: 415.2 (M+H)⁺.

Example 1764-[4-(4-Dimethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₈H₂₀N₄O₂S: 356.13. Found: 357.2 (M+H)⁺.

Example 1774-[4-(4-Diethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₂₀H₂₄N₄O₂S: 384.16. Found: 385.2 (M+H)⁺.

Example 1784-Ethyl-6-[5-mercapto-4-(4-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol

ESMS clcd for C₂₀H₂₂N₄O₃S: 398.14. Found: 399.2 (M+H)⁺.

Example 1794-Ethyl-6-[4-(4-imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol

ESMS clcd for C₁₉H₁₇N₅O₂S: 379.11. Found: 380.2 (M+H)⁺.

Example 1804-[4-(2,5-Diethoxy-4-morpholin-4-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₂₄H₃₀N₄O₅S: 486.19. Found: 487.3 (M+H)⁺.

Example 1814-Ethyl-6-{4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

ESMS clcd for C₂₃H₃₀N₄O₃S: 442.20. Found: 443.3 (M+H)⁺.

Example 1824-[4-(4-Dimethylamino-3-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₉H₂₂N₄O₃S: 386.14. Found: 387.2 (M+H)⁺.

Example 1834-Ethyl-6-[5-mercapto-4-(3-pyrrolidin-1-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol

ESMS clcd for C₂₀H₂₂N₄O₂S: 382.15. Found: 383.2 (M+H)⁺.

Example 1844-[4-(3-Dimethylamino-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₈H₂₀N₄O₂S: 356.13. Found: 357.2 (M+H)⁺.

Example 1854-Ethyl-6-{4-[3-(isopropyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

ESMS clcd for C₂₁H₂₆N₄O₃S: 414.17. Found: 415.2 (M+H)⁺.

Example 1864-[4-(3-Dimethylamino-4-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₉H₂₂N₄O₃S: 386.14. Found: 387.2 (M+H)⁺.

Example 1874-Ethyl-6-{4-[3-(ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

ESMS clcd for C₂₀H₂₄N₄O₃S: 400.16. Found: 401.2 (M+H)⁺.

Example 1884-Isopropyl-6-{4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

ESMS clcd for C₂₄H₃₂N₄O₃S: 456.22. Found: 457.3 (M+H)⁺.

Example 1894-Ethyl-6-{4-[3-(ethyl-isopropyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

ESMS clcd for C₂₂H₂₈N₄O₃S: 428.19. Found: 429.3 (M+H)⁺.

Example 1904-Ethyl-6-[5-mercapto-4-(4-methoxy-3-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol

ESMS clcd for C₂₁H₂₄N₄O₄S: 428.15. Found: 429.2 (M+H)⁺.

Example 1914-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H); 9.39 (s, 1H); 6.92-6.83(m, 3H); 6.56(d, J=1.8 Hz, 1H); 6.23 (s, 1H); 3.74 (s, 3H); 3.0-2.93(m,1H); 2.81(t, J=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d,J=6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H);

ESMS clcd for C₂₂H₂₈N₄O₃S: 428.19. Found: 429.2 (M+H)⁺.

Example 1924-{4-[3-(Ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H); 9.40 (s, 1H); 6.92-6.85(m, 3H); 6.58 (d, J=1.8 Hz, 1H); 6.24 (s, 1H); 3.76 (s, 3H); 3.02-2.90(m, 3H); 2.49 (s, 3H) 0.99 (d, J=6.9 Hz, 6H); 0.86 (t, J=7.2 Hz, 3H).

ESMS clcd for C₂₁H₂₆N₄O₃S: 414.17. Found: 415.1 (M+H)⁺.

Example 1934-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[methyl-(3-methyl-butyl)-amino]-phenyl}-4H-[1,2,4]triazol-3-yl)-benzene-1,3-diol

ESMS clcd for C₂₄H₃₂N₄O₃S: 456.22. Found: 457.2 (M+H)⁺.

Example 1944-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol;compound with hydrogen chloride

ESMS clcd for C₂₂H₂₉ClN₄O₃S: 464.16. Found: 429.3 (M+H)⁺.

Example 1954-{4-[3-(Butyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol

ESMS clcd for C₂₃H₃₀N₄O₃S: 442.20. Found: 443.3 (M+H)⁺.

Example 1964-{4-[3-(Isobutyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol

ESMS clcd for C₂₃H₃₀N₄O₃S: 442.20. Found: 443.1 (M+H)⁺.

Example 1974-(4-{3-[(2-Imidazol-1-yl-ethyl)-methyl-amino]-4-methoxy-phenyl}-5-mercapto-4H-[1,2,4]triazol-3-yl)-6-isopropyl-benzene-1,3-diol

ESMS clcd for C₂₄H₂₈N₆O₃S: 480.19. Found: 481.1 (M+H)⁺.

Example 1984-(4-(3-(1H-pyrrol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol

ESMS clcd for C₂₀H₁₈N₄O₂S: 378.12. Found: 379.1 (M+H)⁺.

Example 1994-(4-(4-(1H-pyrazol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol

ESMS clcd for C₁₉H₁₇N₅O₂S: 379.11. Found: 380.1 (M+H)⁺.

Example 2004-(4-(3-(dimethylamino)-4-(methylthio)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol

ESMS clcd for C₂₀H₂₄N₄O₂S₂: 416.13. Found: 417.1 (M+H)⁺.

Example 2014-isopropyl-6-(5-mercapto-4-(4-methoxy-3-(propylamino)phenyl)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol

ESMS clcd for C₂₁H₂₆N₄O₃S: 414.17. Found: 415.1 (M+H)⁺.

Example 2024-[4-(4-Amino-3-hydroxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₆H₁₆N₄O₃S: 344.09. Found: 345.1 (M+H)⁺.

Example 2034-ethyl-6-(4-(3-hydroxy-4-(methylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)benzene-1,3-diol

ESMS clcd for C₁₇H₁₈N₄O₃S: 358.11. Found: 359.1 (M+H)⁺

Example 2044-(4-(3-aminophenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-diol

ESMS clcd for C₁₆H₁₆N₄O₂S: 328.10. Found: 329.1 (M+H)⁺.

Example 2054-[4-(4-Dimethylamino-3-methyl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-ethyl-benzene-1,3-diol

ESMS clcd for C₁₉H₂₃N₄O₂S: 371.1. Found: 371.1 (M+H)⁺.

Example 2064-[4-(3-Imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-isopropyl-benzene-1,3-diol

ESMS clcd. for C₂₀H₂₀N₅O₂S: 394.1. Found: 394.1 (M+H)⁺.

Example 2074-[4-(3-Imidazol-1-yl-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-isopropyl-benzene-1,3-diol

2-{3-[3-(2,4-Dihydroxy-5-isopropyl-phenyl)-5-mercapto-[1,2,4]triazol-4-yl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.63 (br s, 1H); 7.70-7.80 (m, 2H);7.37-7.43 (m, 1H); 6.99-7.02 (m, 1H); 6.91 (s, 1H); 6.25 (s, 1H); 5.35(s, 1H); 3.70 (s, 2H); 2.96 (hept, J=6.9 Hz, 1H); 2.09 (s, 3H); 0.99 (d,J=6.9 Hz, 6H);

ESMS clcd. for C₂₁H₂₂N₅O₃S: 424.1. Found: 424.1 (M+H)⁺.

Example 208 Inhibition of Hsp90

Hsp90 protein was obtained from Stressgen (Cat#SPP-770). Assay buffer:100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl₂. Malachite green (0.0812%w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (P1097) were obtainedfrom Sigma. A Malachite Green Assay (see Methods Mol Med, 2003, 85:149for method details) was used for examination of ATPase activity of Hsp90protein. Briefly, Hsp90 protein in assay buffer (100 mM Tris-HCl, Ph7.4,20 mM KCl, 6 mM MgCl₂) was mixed with ATP alone (negative control) or inthe presence of Geldanamycin (a positive control) or Compound 108 in a96-well plate. Malachite green reagent was added to the reaction. Themixtures were incubated at 37° C. for 4 hours and sodium citrate buffer(34% w/v sodium citrate) was added to the reaction. The plate was readby an ELISA reader with an absorbance at 620 nm.

As can be seen in FIG. 1, 40 μM of geldanamycin, a natural product knownto inhibit Hsp90 activity, the ATPase activity of Hsp90 was onlyslightly higher than background. 40 μM Compound 108 showed an evengreater inhibition of ATPase activity of Hsp90 than geldanamycin, andeven at 4 μM Compound 108 showed significant inhibition of ATPaseactivity of Hsp90 protein.

Example 209 Degradation of Client Proteins Via Inhibition of Hsp90Activity

A. Cells and Cell Culture

Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) andMCF-7 breast carcinoma (HTB-22) from American Type Culture Collection,VA, USA were grown in Dulbecco's modified Eagle's medium with 4 mML-glutamine and antibiotics (100 IU/ml penicillin and 100 ug/mlstreptomycine; GibcoBRL). To obtain exponential cell growth, cells weretrypsinized, counted and seeded at a cell density of 0.5×10⁶ cells/mlregularly, every 3 days. All experiments were performed on day 1 aftercell passage.

B. Degradation of Her2 in Cells after Treatment with a Compound of theInvention

-   -   1. Method 1

BT-474 cells were treated with 0.5 μM, 2 μM, or 5 μM of 17AAG (apositive control) or 0.5 μM, 2 μM, or 5 μM of Compound 108 or Compound49 overnight in DMEM medium. After treatment, each cytoplasmic samplewas prepared from 1×10⁶ cells by incubation of cell lysis buffer (#9803,cell Signaling Technology) on ice for 10 minutes. The resultingsupernatant used as the cytosol fractions were dissolved with samplebuffer for SDS-PAGE and run on a SDS-PAGE gel, blotted onto anitrocellulose membrane by using semi-dry transfer. Non-specific bindingto nitrocellulose was blocked with 5% skim milk in TBS with 0.5% Tweenat room temperature for 1 hour, then probed with anti-Her2/ErB2 mAb(rabbit IgG, #2242, Cell Signaling) and anti-Tubulin (T9026, Sigma) ashousekeeping control protein. HRP-conjugated goat antirabbit IgG (H+L)and HRP-conjugated horse anti-mouse IgG (H+L) were used as secondary Ab(#7074, #7076, Cell Signaling) and LumiGLO reagent, 20× Peroxide (#7003,Cell Signaling) was used for visualization.

As can be seen from FIG. 2, Her2, an Hsp90 client protein, is almostcompletely degraded when cells are treated with 5 μM of Compound 108 andpartially degradated when cells are treated with 2 μM and 0.5 μM ofCompound 108. Compound 49 which is even more active than Compound 108causes complete degradation of Her2 when cells are treated with 2 μM and5 μM and causes partial degradated when cells are treated with 0.5 μM17AAG is a known Hsp90 inhibitor and is used as a positive control.

2. Method 2

MV-4-11 cells (20,000 cells/well) are cultured in 96-well plates andmaintained at 37° C. for several hours. The cells are treated with acompound of the invention or 17AAG (a positive control) at variousconcentrations and incubated at 37° C. for 72 hours. Cell survival ismeasured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. #CK04).

TABLE 8 IC₅₀ range of compounds of the invention for inhibition of Her2degradation IC₅₀ Range Compound Number <3 μM 8, 13, 39, 49, 63, 76, 77,79, 87, 88, 95, 96, 100, 103, 177, 178, 185, 188, 189, 247, 248, 249,250, 251, 252, 259 3 μM to 10 μM 2, 5, 6, 7, 9, 14, 27, 28, 34, 36, 38,42, 48, 64, 70, 93, 97, 108, 122, 183, 184 10 μM to 100 μM 21, 22, 30,51, 59, 60, 61, 62, 94, 98, 99, 102, 104, 123, 181, 182, 186, 187, 348

C. Fluorescent Staining of Her2 on the Surface of Cells Treated with aCompound of the Invention

After treatment with a compound of the invention, cells were washedtwice with 1×PBS/1% FBS, and then stained with anti-Her2-FITC (#340553,BD) for 30 min at 4° C. Cells were then washed three times in FACSbuffer before the fixation in 0.5 ml 1% paraformadehydrede. Data wasacquired on a FACSCalibur system. Isotype-matched controls were used toestablish the non-specific staining of samples and to set thefluorescent markers. A total 10,000 events were recorded from eachsample. Data were analysed by using CellQuest software (BD Biosciences).The IC₅₀ range for Hsp90 inhibition by compounds of the invention arelisted below in Table 2.

D. Apoptosis Analysis

After treatment with the compounds of the invention, cells were washedonce with 1×PBS/1% FBS, and then stained in binding buffer withFITC-conjugated Annexin V and Propidium iodide (PI) (all obtained fromBD Biosciences) for 30 min at 4° C. Flow cytometric analysis wasperformed with FACSCalibur (BD Biosciences) and a total 10,000 eventswere recorded from each sample. Data were analyzed by using CellQuestsoftware (BD Biosciences). The relative fluorescence was calculatedafter subtraction of the fluorescence of control.

E. Degradation of c-Met in NCI-H1993 Cells after Treatment with aCompound of the Invention

We examined the ability of the Hsp90 inhibitors of the invention toinduce the degradation of c-Met, an Hsp90 client protein that isexpressed at high levels in several types of cancer. A non-small celllung cancer cell line, NCI-H1993 (ATCC, cat#CRL-5909), which expressesc-met at high levels, was seeded in 6-well plates at 5×10⁵ cells/well.The cells were either untreated (lane 2), treated with STA-4783, acompound that does not inhibit Hsp90 (control, lane 3), or treated with17AAG (400 nM (lane 4) or 100 nM (lane 5), Compound 221 (400 nM (lane 6)or 100 nM (lane 7)), Compound 257 (400 nM (lane 8) or 100 nM (lane 9))or Compound 258 (400 nM (lane 10) or 100 nM (lane 11)). After 24 hours,the cells were lysed and an equal amount of protein from each treatmentgroup was used for Western blot analysis. The Western blot shown in FIG.3 indicates that compounds of the invention potently induced degradationof c-Met due to inhibition.

F. Degradation of c-Met in ACHN and MKN-45 Cells after Treatment with aCompound of the Invention

Flow cytometric analysis was used to monitor the degradation of c-Metover-expressed on the surface of the ACHN human renal cell carcinomacell line which contains the juxtamembrane domain mutation (C3223T:T1010I) and is constitutively active, and the MKN45 which is a c-Metamplified human gastric carcinoma cell line. ACHN and MKN45 cells (5×10⁵cells) were treated with Compound 226, 17-AAG or 17-DMAG for 18 hours.After treatment the cells were stained with FITC conjugated c-METantibody. The expression of the c-Met cell surface proteins was measuredby flow cytometry analysis (see FIG. 4 for ACHN cells and FIG. 5 forMKN45 cells). The IC₅₀ value was determined by XLfit software. Compound226 potently induced the degradation of mutant c-Met with an IC₅₀ valueof 18 nM. In contrast, 17-AAG was about ten folds less affective atinduce c-Met degradation (IC₅₀ value of 244 nM), and 17-DMAG was aboutfive folds less affective (IC₅₀ value of 95 nM). In the MKN-45 cellline, Compound 226 induced the degradation of c-Met (26 nM) with agreater potency than 17-AAG (202 nM IC₅₀) and 17-DMAG (70 nM).

Example 210 Evaluation of IC₅₀ for Cell Survival in Cells Treated withHsp90 Inhibitors

MNK45 cell line, (DSMZ #ACC 409), which is a c-Met amplified humangastric carcinoma cell line, was obtained from the Deutsche Sammlung vonMikroorganismen and Zellkulturen GmbH (DSMZ; Braunschweig, Germany).Growth of this tumor cell line is dependent upon the expression of anamplified c-Met locus (G. A. Smolen et al., Proc. Natl. Acad. Sci. USA103:2316-2321, 2006). MNK45 cells (20,000 cells/well) were cultured in96-well plates and maintained at 37° C. for several hours. The cellswere incubated at 37° C. for 72 hours with various concentrations ofcompound 226 of the invention, 17AAG, or DMAG. 17AAG and 17DMAG areHsp90 inhibitors that are currently in clinical trials and are used hereas positive controls for Hsp90 inhibition. Cell survival was measuredwith Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can beseen from FIG. 6, compound 226 of the invention had a lower IC₅₀ forcell survival than either 17AAG or DMAG. The IC₅₀ values are shown inthe table below:

Compound IC₅₀ (μM) 17AAG 0.045 DMAG 0.014 Compound 226 0.008

Example 211 Compound 49 Displays Anti-Tumor Activity Against the HumanTumor Cell Line MDA-MB-435S in a Nude Mouse Xenograft Model

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), was obtained from the American TypeCulture Collection (Manassas, Va., USA). The cell line was cultured ingrowth media prepared from 50% Dulbecco's Modified Eagle Medium (highglucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100× Penicillin-Streptomycin, 1% 100× sodium pyruvateand 1% 100× MEM non-essential amino acids. FBS was obtained fromSigma-Aldrich Corp. (St. Louis, Mo., USA), and all other reagents wereobtained from Invitrogen Corp. (Carlsbad, Calif., USA). Approximately4-5×10(6) cells that had been cryopreserved in liquid nitrogen wererapidly thawed at 37° C. and transferred to a 175 cm² tissue cultureflask containing 50 ml of growth media and then incubated at 37° C. in a5% CO₂ incubator. The growth media was replaced every 2-3 days until theflask became 90% confluent, typically in 5-7 days. To passage and expandthe cell line, a 90% confluent flask was washed with 10 ml of roomtemperature phosphate buffered saline (PBS) and the cells weredisassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) and incubatingat 37° C. until the cells detached from the surface of the flask. Toinactivate the trypsin, 5 ml of growth media was added and then thecontents of the flask were centrifuged to pellet the cells. Thesupernatant was aspirated and the cell pellet was resuspended in 10 mlof growth media and the cell number determined using a hemocytometer.Approximately 1-3×10(6) cells per flask were seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reached 90% confluence, the above passagingprocess was repeated until sufficient cells had been obtained forimplantation into mice.

Six to eight week old, female Crl:CD-1-nuBR (nude) mice were obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals werehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies were conducted on animals between 7 and 12weeks of age at implantation. To implant tumor cells into nude mice, thecells were trypsinized as above, washed in PBS and resusupended at aconcentration of 50×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension was injected into the corpusadiposum of nude mice. The corpus adiposum is a fat body located in theventral abdominal vicera in the right quadrant of the abdomen at thejuncture of the os coxae (pelvic bone) and the os femoris (femur).Tumors were then permitted to develop in vivo until they reachedapproximately 150 mm³ in volume, which typically required 2-3 weeksfollowing implantation. Tumor volumes (V) were calculated by calipermeasurement of the width (W), length (L) and thickness (T) of tumorsusing the following formula: V=0.5326×(L×W×T) Animals were randomizedinto treatment groups so that the average tumor volumes of each groupwere similar at the start of dosing.

Sock solutions of test compounds were prepared by dissolving theappropriate amounts of each compound in dimethyl sulfoxide (DMSO) bysonication in an ultrasonic water bath. Stock solutions were prepared atthe start of the study, stored at −20° C. and diluted fresh each day fordosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Ill.,USA) was also prepared by first heating 100% Cremophore RH40 at 50-60°C. until liquefied and clear, diluting 1:5 with 100% D5W, reheatingagain until clear and then mixing well. This solution was stored at roomtemperature for up to 3 months prior to use. To prepare formulations fordaily dosing, DMSO stock solutions were diluted 1:10 with 20% CremophoreRH40. The final formulation for dosing contained 10% DMSO, 18%Cremophore RH40, 3.6% dextrose and 68.4% water and the appropriateamount of test article. Animals were intraperitoneal (IP) injected withthis solution at 10 ml per kg body weight on a schedule of 5 days perweek (Monday thru Friday, with no dosing on Saturday and Sunday) for 3weeks.

As shown in FIG. 4, treatment with 300 mg/kg body weight of Compound 49decreased the growth rate of MDA-MB-435S cells in nude mice to a greaterextent than did a dose of 100 mg/kg body weight of the Hsp90 inhibitor17-AAG. This effect was not associated with significant toxicity, asshown by the lack of an effect on body weights (FIG. 5).

Example 212 Compound #226 Displays Anti-Tumor Activity Against HumanTumor Cells Having an Amplified c-MET Locus in a Mouse Xenograft Model

The human gastric carcinoma cell line, MKN-45 (DSMZ #ACC 409), wasobtained from the Deutsche Sammlung von Mikroorganismen and ZellkulturenGmbH (DSMZ; Braunschweig, Germany). Growth of this tumor cell line isdependent upon the expression of an amplified c-Met locus (G. A. Smolenet al., Proc. Natl. Acad. Sci. USA 103:2316-2321, 2006). The cells werecultured in growth media prepared with RPMI Media 1640 (high glucose),20% fetal bovine serum (FBS), 1% 100× Penicillin-Streptomycin, 1% 100×sodium pyruvate and 1% 100× MEM non-essential amino acids. FBS wasobtained from ATCC and all other reagents were obtained from InvitrogenCorp. (Carlsbad, Calif., USA). Cells that had been cryopreserved inliquid nitrogen were rapidly thawed at 37° C. and transferred to atissue culture flask containing growth media and then incubated at 37°C. in a 5% CO₂ incubator. To expand the cell line, growth media wasreplaced every 2-3 days until the flask became 90% confluent, typicallyin 5-10 days. Cultures were passaged by washing with 10 mL of roomtemperature phosphate buffered saline (PBS) and then disassociatingcells by adding 5 mL 1× trypsin-EDTA and incubating at 37° C. until thecells detached from the surface of the flask. To inactivate the trypsin,5 mL of growth media was added and then the contents of the flask werecentrifuged to pellet the cells. The supernatant was aspirated and thecell pellet was resuspended in 10 mL of growth media and the cell numberdetermined using a hemocytometer. Approximately 3-6×10(6) cells perflask were seeded into 175 cm² flasks containing 50 mL of growth mediaand incubated at 37° C. in a 5% CO₂ incubator. When the flasks reached90% confluence, the above passaging process was repeated untilsufficient cells had been obtained for implantation into mice.

Seven to eight week old, female Crl:CD-1-Foxn1^(nu) (nude) mice wereobtained from Charles River Laboratories (Wilmington, Mass., USA)Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hrlight/dark cycle, acclimated for at least 1 week prior to use and fednormal laboratory chow ad libitum. Animals were between 18 and 19 weeksof age at implantation. To implant MKN-45 tumor cells into nude mice,cell cultures were trypsinized as above, washed in PBS and resusupendedat a concentration of ˜5-10×10(7) cells/mL in 50% non-supplemented RPMIMedia 1640 (high glucose) and 50% Matrigel Basement Membrane Matrix(#354234; BD Biosciences; Bedford, Mass., USA). Using a 27 gauge needleand 1 cc syringe, 0.1 mL of the cell suspension was injectedsubcutaneously into the flanks of nude mice.

Tumors were then permitted to develop in vivo until the majority reached100-200 mm³ in tumor volume, which required ˜2 weeks followingimplantation. Animals with oblong, very small or large tumors werediscarded and only animals carrying tumors that displayed consistentgrowth rates were selected for studies. Tumor volumes (V) werecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals were randomized into treatment groups so that the average tumorvolumes of each group were similar at the start of dosing. % T/C values,as a measure of efficacy, were determined as follows:

-   -   (i) If ΔT>0: % T/C=(ΔT/ΔC)×100    -   (ii) If ΔT<0: % T/C=(ΔT/T₀)×100    -   (iii) ΔT=Change in average tumor volume between start of dosing        and the end of study.    -   (iv) ΔC=Change in average tumor volume between start of dosing        and the end of study.    -   (v) T₀=Average tumor volume at start of dosing.

To formulate Compound #226 in DRD, stock solutions of the test articlewere prepared by dissolving the appropriate amounts of the compound indimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath.Stock solutions were prepared weekly, stored at −20° C. and dilutedfresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft,Ludwigshafen, Germany) in 5% dextrose in water (Abbott Laboratories,North Chicago, Ill., USA) was also prepared by first heating 100%Cremophore RH40 at 50-60° C. until liquefied and clear, diluting 1:5with 100% D5W, reheating again until clear and then mixing well. Thissolution can be stored at room temperature for up to 3 months prior touse. To prepare DRD formulations for daily dosing, DMSO stock solutionswere diluted 1:10 with 20% Cremophore RH40. The final DRD formulationfor dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4%water and the appropriate amount of test article. Animals wereintravenously (i.v.) injected with this formulation at 10 mL per kg bodyweight on three days each week (Monday, Wednesday, Friday) for a totalof 9 doses.

As shown in FIG. 7, treatment 3 times per week with a dose of 50 mg/kgbody weight of Compound #226 substantially decreased the growth rate ofMKN-45 cells in nude mice, with a % T/C value of 8. This effect was notassociated with excessive toxicity, as dose group treated with 50 mg/kgCompound #226 had an average body weight loss of −3.5% (+/−0.8 SEM) overthe course of the study.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

What is claimed:
 1. A method of treating a c-Met associated cancer in asubject, comprising administering to the subject an effective amount ofa compound represented by formula (XVIII):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R₁is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR7)₂, or—SP(O)(OR₇)₂; R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆,—O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith: i) one substituent selected from nitro, cyano, a haloalkoxy, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxylalkyl, alkoxyalkyl, guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇,—C(O)OR₂₀, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or ii)two to five substituents selected from the group consisting of anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro,guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₆,for each occurrence, is independently a substituent selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₂₀, for each occurrence, is independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; R₂₆ is a lower alkyl; p, for each occurrence, is,independently, 0, 1 or 2; n is zero of an interger from 1 to 4; and m,for each occurrence, is independently, 1, 2, 3, or 4, wherein the c-Metassociated cancer has developed a resistance to treatment with atyrosine kinase inhibitor.
 2. The method of claim 1, wherein thetyrosine kinase inhibitor inhibits the kinase activity of c-Met.
 3. Themethod of claim 1, wherein the tyrosine kinase inhibitor does notsubstantially inhibit the kinase activity of c-Met.
 4. A method oftreating a c-Met associated cancer in a subject, comprisingadministering to the subject an effective amount of a compoundrepresented by formula (XVIII):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R₁is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR7)₂, or—SP(O)(OR₇)₂; R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆,—O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith: i) one substituent selected from nitro, cyano, a haloalkoxy, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxylalkyl, alkoxyalkyl, guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇,—C(O)OR₂₀, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or ii)two to five substituents selected from the group consisting of anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano, nitro,guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₆, for each occurrence, is independently a substituent selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₂₀, for each occurrence, is independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; R₂₆ is a lower alkyl; p, for each occurrence, is,independently, 0, 1 or 2; n is zero of integer from 1 to 4; and m, foreach occurrence, is independently, 1, 2, 3, or 4, wherein the cancer hasmutations or deletions in the kinase or juxtamembrane domain of c-Met,amplification of the Met gene, or overexpression of c-Met.